Neisseria and Related Genera Notes

Neisseria

A 22-year-old woman presented with fever, chills, headache, and a maculopapular rash.
Elevated leukocyte count and sedimentation rate were noted.
Blood cultures were positive for gram-negative diplococci after 10 hours.
Likely infection: Neisseria gonorrhoeae or Neisseria meningitidis.
Additional tests are needed for definitive identification.

Neisseria gonorrhoeae and Neisseria meningitidis

Most important members of the Neisseria genus.
Neisseria is differentiated from other bacteria via growth properties.
Major virulence factors differ for each organism.
Vaccine exists for N. meningitidis but not N. gonorrhoeae.
N. meningitidis vaccine does not cover all serogroups.

Neisseria gonorrhoeae

Trigger words: Diplococci, gonorrhea, arthritis, ophthalmia.
Gram-negative diplococci with fastidious growth requirements.
Optimal growth at 35°C-37°C in a humid atmosphere with CO2.
Oxidase and catalase positive; produces acid from glucose oxidatively.
Outer surface antigens: pili protein, Por proteins, Opa proteins, Rmp protein, receptors for transferrin, lactoferrin, and hemoglobin, lipooligosaccharide, immunoglobulin protease, β-lactamase.
Humans are the only natural hosts.
Asymptomatic carriage is possible in women.
Transmission is primarily via sexual contact.
Approximately 555,608 cases were reported in the United States in 2017; an estimated 78 million new cases worldwide.
Most common in blacks, people aged 15-24 years, residents of southeastern United States, and people with multiple sexual encounters.
Higher risk of disseminated disease in patients with complement deficiencies.
Gram stain of urethral specimens is accurate for symptomatic males only.
Culture is sensitive and specific but has been replaced by nucleic acid tests in most laboratories.
Treatment: ceftriaxone with azithromycin.
Neonates: prophylaxis with 1% silver nitrate; treat ophthalmia neonatorum with ceftriaxone.
Prevention: patient education, condoms or spermicides with nonoxynol-9, and aggressive follow-up of sexual partners.
Effective vaccines are not available.

Neisseria meningitidis

Trigger words: Diplococci, meningitis, meningococcemia, pneumonia, vaccine.
Gram-negative diplococci with fastidious growth requirements.
Optimal growth at 35°C-37°C in a humid atmosphere.
Oxidase and catalase positive; produces acid from carbohydrates oxidatively.
Outer surface antigens: polysaccharide capsule, pili, and lipooligosaccharides.
Capsule protects bacteria from antibody-mediated phagocytosis.
Specific receptors for meningococcal pili allow colonization of the nasopharynx.
Bacteria can survive intracellular killing in the absence of humoral immunity.
Endotoxin mediates most clinical manifestations.
Humans are the only natural hosts.
Person-to-person spread occurs via aerosolization of respiratory tract secretions.
Highest incidence in children younger than 1 year old, institutionalized people, and patients with late complement deficiencies.
Endemic and epidemic disease is most commonly caused by serogroups A, B, C, W135, X, and Y; pneumonia is most commonly caused by serogroups Y and W135.
Disease occurs worldwide, most commonly in the dry, cold months of the year.
Gram stain of cerebrospinal fluid is sensitive and specific.
Culture is definitive, but the organism is fastidious.
Tests to detect meningococcal antigens are insensitive and nonspecific.
Breast-feeding infants have passive immunity (first 6 months).
Empirical treatment: ceftriaxone.
Chemoprophylaxis: rifampin, ciprofloxacin, or ceftriaxone.
Immunoprophylaxis: vaccination is used only for serogroups A, C, Y, and W135; no effective vaccine is available for serogroup B.

Important Neisseriaceae Genera

Neisseria

Named after Albert Neisser.

N. gonorrhoeae

"gone," seed; "rhoia," a flow (reference to gonorrhea).

N. meningitidis

"meningis," the covering of the brain; "itis," inflammation (meningitis).

Eikenella

Named after M. Eiken.

E. corrodens

"corrodens," gnawing or eating (colonies pit the agar).

Kingella

Named after Elizabeth King.

Neisseria and Related Genera

Three genera of medically important bacteria in the family Neisseriaceae: Neisseria, Eikenella, and Kingella.
The genus Neisseria consists of 35 species and subspecies.
Two species, Neisseria gonorrhoeae and Neisseria meningitidis, are strictly human pathogens.
Additional species are commonly present on mucosal surfaces of the oropharynx and nasopharynx.
Diseases caused by N. gonorrhoeae and N. meningitidis are well known.
Other Neisseria species have limited virulence and generally produce opportunistic infections.
Eikenella corrodens and Kingella kingae colonize the human oropharynx and are also opportunistic pathogens.

Neisseria gonorrhoeae and Neisseria meningitidis

Infections caused by N. gonorrhoeae have been recognized for centuries.
Gonorrhea is still one of the most common sexually transmitted diseases in the United States.
The presence of N. gonorrhoeae in a clinical specimen is always considered significant.
Strains of N. meningitidis can colonize the nasopharynx of healthy people without producing disease.

Physiology and Structure

Neisseria species are aerobic gram-negative bacteria, typically coccoid-shaped (0.6 to 1.0 µm in diameter) and arranged in pairs (diplococci).
All species are oxidase positive, and most produce catalase.
Acid is produced by oxidation of carbohydrates (not by fermentation).
Pathogenic and nonpathogenic species of Neisseria can also be differentiated by their growth on blood agar and nutrient agar.
Nonpathogenic strains grow on both media, N. meningitidis grows on blood agar and has variable growth on nutrient agar, and N. gonorrhoeae typically does not grow on either media.
Strains of N. gonorrhoeae require cystine and an energy source (e.g., glucose, pyruvate, lactate) for growth, and many strains require supplementation of media with amino acids, purines, pyrimidines, and vitamins.
Soluble starch is added to the media to neutralize the toxic effect of the fatty acids.
Optimum growth temperature is 35°C to 37°C, with poor survival of the organism at cooler temperatures.
A humid atmosphere supplemented with 5% carbon dioxide is either required or enhances growth of N. gonorrhoeae.
The cell wall structure of N. gonorrhoeae and N. meningitidis is typical of gram-negative bacteria.
The major virulence factor for N. meningitidis is the polysaccharide capsule.
Although the outer surface of N. gonorrhoeae is not covered with a true carbohydrate capsule, the cell surface of N. gonorrhoeae has a capsule-like negative charge.
Antigenic differences in the polysaccharide capsule of N. meningitidis are the basis for serogrouping these bacteria in vitro.
Six serogroups (A, B, C, W135, X, and Y) are associated with endemic and epidemic disease.
Pathogenic and nonpathogenic strains of Neisseria have pili that extend from the cytoplasmic membrane through the outer membrane.
Pili mediate a number of functions, including attachment to host cells, transfer of genetic material, and motility.
The lack of immunity to reinfection with N. gonorrhoeae results partially from the antigenic variation among the pilin proteins and partially from the phase variation in pilin expression.
Porin proteins are integral outer membrane proteins that form pores or channels for nutrients to pass into the cell and waste products to exit.
N. gonorrhoeae and N. meningitidis have two porin genes, porA and porB.
PorB is important for the virulence of N. gonorrhoeae because these proteins can interfere with degranulation of neutrophils.
Opa proteins (opacity proteins) are a family of membrane proteins that mediate intimate binding to epithelial and phagocytic cells and are important for cell-to-cell signaling.
The third group of proteins in the outer membrane is the highly conserved Rmp proteins (reduction-modifiable proteins).
These proteins stimulate antibodies that interfere with the serum bactericidal activity against pathogenic neisseriae.

Iron Acquisition

Iron is essential for the growth and metabolism of N. gonorrhoeae and N. meningitidis.
These pathogenic neisseriae bind host cell transferrin to specific bacterial surface receptors.
The gonococci also have a variety of additional surface receptors for other host iron complexes, such as lactoferrin and hemoglobin.
Another major antigen in the cell wall is LOS.
Both N. gonorrhoeae and N. meningitidis spontaneously release outer membrane blebs during rapid cell growth.
N. gonorrhoeae and N. meningitidis produce immunoglobulin (Ig)A1 protease, which cleaves the hinge region in IgA1.
Some strains of N. gonorrhoeae also produce β-lactamase that can degrade penicillin.

Pathogenesis and Immunity

Gonococci attach to mucosal cells, penetrate into the cells and multiply, and then pass through the cells into the subepithelial space in which infection is established.
Pili, PorB, and Opa proteins mediate attachment and penetration into host cells.
The gonococcal LOS stimulates release of the proinflammatory cytokine TNF-α, which causes most of the symptoms associated with gonococcal disease.
IgG3 is the predominant IgG antibody formed in response to gonococcal infection.
Presence of the capsule interferes with epithelial cell attachment, so synthesis is downregulated before attachment.
Meningococcal disease occurs in patients who lack specific antibodies directed against the polysaccharide capsule and other expressed bacterial antigens.
Infants are initially afforded protection by the passive transfer of maternal antibodies.
Patients with deficiencies in C5, C6, C7, or C8 of the complement system are estimated to be at a 6000-fold greater risk for meningococcal disease.
Similar to N. gonorrhoeae, meningococci are internalized into phagocytic vacuoles and are able to avoid intracellular death, replicate, and then migrate to the subepithelial spaces.
The polysaccharide capsule protects N. meningitidis from phagocytic destruction.
The diffuse vascular damage associated with meningococcal infections is largely attributed to the action of the LOS endotoxin present in the outer membrane.

Epidemiology

Gonorrhea occurs naturally only in humans.
It is second only to chlamydia as the most commonly reported sexually transmitted disease in the United States.
Infection rates are the same in males and females, are disproportionately higher in blacks than in Hispanic Americans and whites, and are highest in the southeastern United States.
The peak incidence of the disease is in the age group of 15 to 24 years.
In 2017, 555,608 new infections were reported in the United States.
N. gonorrhoeae is transmitted primarily by sexual contact.
Women have a 50% risk of acquiring the infection as the result of a single exposure to an infected man, whereas men have a risk of approximately 20% as the result of a single exposure to an infected woman.
The major reservoir for gonococci is the asymptomatically infected person.
Endemic meningococcal disease occurs worldwide, and epidemics are common in developing countries.
Of the 13 serogroups, almost all infections are caused by serogroups A, B, C, W135, X, and Y.
N. meningitidis is transmitted by respiratory droplets among people in prolonged close contact.
Humans are the only natural carriers for N. meningitidis.
Carriage is typically transient, with clearance occurring after specific antibodies develop.
Disease is most common in children younger than 1 year old, with a second peak in adolescence.

Clinical Diseases

Neisseria gonorrhoeae

Genital infection: primarily restricted to the urethra in men.

Purulent urethral discharge and dysuria develop after a 2- to 5-day incubation period.
Ascending genital infections, including salpingitis, tuboovarian abscesses, and PID, are observed in 10% to 20% of women.

Gonococcemia

Disseminated infections with septicemia and infection of skin and joints occur in 1% to 3% of infected women and in a much lower percentage of infected men.
Clinical manifestations include fever; migratory arthralgias; suppurative arthritis in the wrists, knees, and ankles; and a pustular rash on an erythematous base over the extremities but not on the head and trunk.
N. gonorrhoeae is a leading cause of purulent arthritis in adults.

Other Neisseria gonorrhoeae Syndromes

Diseases associated with N. gonorrhoeae are perihepatitis (Fitz-Hugh–Curtis syndrome); purulent conjunctivitis, particularly in newborns infected during vaginal delivery (ophthalmia neonatorum); anorectal gonorrhea in homosexual men; and pharyngitis.

Neisseria meningitidis

The disease usually begins abruptly with headache, meningeal signs, and fever.

Mortality approaches 100% in untreated patients but is less than 10% in patients in whom appropriate antibiotic therapy is instituted promptly.

Meningococcemia

Septicemia is a life-threatening disease.
Thrombosis of small blood vessels and multiorgan involvement are the characteristic clinical features.
Small, petechial skin lesions on the trunk and lower extremities are common and may coalesce to form larger hemorrhagic lesions.
Overwhelming DIC with shock, together with bilateral destruction of the adrenal glands (Waterhouse-Friderichsen syndrome), may ensue.

Other Neisseria meningitidis Syndromes

Additional infections caused by N. meningitidis are pneumonia, arthritis, and urethritis.
Meningococcal pneumonia is usually preceded by a respiratory tract infection.
Symptoms include cough, chest pain, rales, fever, and chills.

Laboratory Diagnosis

Microscopy

Gram stain is very sensitive (>90%) and specific (98%) in detecting gonococcal infection in men with purulent urethritis.
However, its sensitivity in detecting infection in asymptomatic men is 60% or less.
The test is also relatively insensitive in detecting gonococcal cervicitis in both symptomatic and asymptomatic women.

Antigen Detection

Nucleic Acid–Based Tests

NAATs specific for N. gonorrhoeae were one of the first molecular tests introduced in clinical laboratories and currently represent the diagnostic gold standard.

Culture

N. gonorrhoeae can be readily isolated from genital specimens if care is taken in collecting and processing the specimens.

Identification

Pathogenic Neisseria species are identified preliminarily on the basis of the isolation of oxidase-positive, gram-negative diplococci that grow on chocolate blood agar or on media that are selective for pathogenic Neisseria species.

Treatment, Prevention, and Control

Currently, the Centers for Disease Control and Prevention (CDC) recommends dual therapy with ceftriaxone and azithromycin.
Major efforts to stem the epidemic of gonorrhea encompass education, aggressive detection, and follow-up screening of sexual contacts.
Chemoprophylaxis with 1% silver nitrate, 1% tetracycline, or 0.5% erythromycin eye ointment is routinely used to protect newborns against gonococcal eye infections (ophthalmia neonatorum).
Immunity to infection with N. gonorrhoeae is poorly understood.
Cefotaxime or ceftriaxone should be used initially to treat N. meningitidis infections.
Chemoprophylaxis is recommended for contacts with significant exposure to patients with meningococcal disease (defined as individuals with direct exposure to respiratory secretions or >8 hours of close contact with the patient).
Two tetravalent vaccines effective against serogroups A, C, Y, and W135 are currently licensed in the United States: a polysaccharide vaccine and a polysaccharide-protein conjugate vaccine.

Other Neisseria Species

Neisseria species such as N. sicca and N. mucosa are commensal organisms in the oropharynx.

Eikenella corrodens

It is a moderate-sized (0.2 × 2.0 µm), nonmotile, non–spore-forming, facultatively anaerobic, gram-negative rod.
The organism is named after Eiken, who characterized the bacterium and observed the ability of the organism to pit or “corrode” agar.

Kingella kingae

Kingella species are small gram-negative coccobacilli that morphologically resemble Neisseria species and reside in the human oropharynx.
The bacteria are facultatively anaerobic, ferment carbohydrates, and have fastidious growth requirements.
K. kingae, the most commonly isolated species, has been primarily responsible for septic arthritis in children and endocarditis in patients of all ages.