Chapter 20: The Neisseriae

The family Neisseriaceae includes the genera Neisseria, Kingella, Eikenella, Simonsiella, and Alysiella (see Chapter 16). The neisseriae are gram-negative cocci that usually occur in pairs (diplococci). Neisseria gonorrhoeae (gonococci) and Neisseria meningitidis (meningococci) are pathogenic for humans and typically are found associated with or inside polymorphonuclear cells. Some neisseriae are normal inhabitants of the human respiratory tract, rarely if ever cause disease, and occur extracellularly. Members of the group are listed in Table 20-1.

Gonococci and meningococci are closely related, with 70% DNA homology, and are differentiated by a few laboratory tests and specific characteristics. Meningococci have polysaccharide capsules but gonococci do not, and meningococci rarely have plasmids but most gonococci do. Most importantly, the two species are differentiated by the usual clinical presentations of the diseases they cause: Meningococci typically are found in the upper respiratory tract and cause meningitis, but gonococci cause genital infections. However, the clinical spectra of the diseases caused by gonococci and meningococci do overlap.

Morphology and Identification

A. Typical Organisms

The typical Neisseria is a gram-negative, nonmotile diplococcus, approximately 0.8 μm in diameter (Figures 20-1 and 20-2). Individual cocci are kidney bean shaped; when the organisms occur in pairs, the flat or concave sides are adjacent.

B. Culture

In 48 hours on enriched media (eg, modified Thayer-Martin, Martin-Lewis, GC-Lect, and New York City), gonococci and meningococci form convex, glistening, elevated, mucoid colonies 1–5 mm in diameter. Colonies are transparent or opaque, nonpigmented, and nonhemolytic. Neisseria flavescens, Neisseria cinerea, Neisseria subflava, and Neisseria lactamica may have yellow pigmentation. Neisseria sicca produces opaque, brittle, wrinkled colonies. Moraxella catarrhalis produces nonpigmented or pinkish gray opaque colonies.

C. Growth Characteristics

The neisseriae grow best under aerobic conditions, but some grow in an anaerobic environment. They have complex growth requirements. Most neisseriae oxidize carbohydrates, producing acid but not gas, and their carbohydrate patterns are a means of distinguishing them (see Table 20-1). The neisseriae produce oxidase and give positive oxidase reactions; the oxidase test is a key test for identifying them. When bacteria are spotted on a filter paper soaked with tetramethylparaphenylenediamine hydrochloride (oxidase), the neisseriae rapidly turn dark purple.

Meningococci and gonococci grow best on media containing complex organic substances such as heated blood, hemin, and animal proteins and in an atmosphere containing 5% CO₂ (eg, candle jar). Growth is inhibited by some toxic constituents of the medium (eg, fatty acids or salts). The organisms are rapidly killed by drying, sunlight, moist heat, and many disinfectants. They produce autolytic enzymes that result in rapid swelling and lysis in vitro at 25°C and at an alkaline pH.

Gonococci oxidize only glucose and differ antigenically from the other neisseriae. Gonococci usually produce smaller colonies than those of the other neisseriae. Gonococci that require arginine, hypoxanthine, and uracil (Arg⁻, Hyx⁻, and Ura⁻ auxotype) tend to grow most slowly on primary culture. Gonococci isolated from clinical specimens or maintained by selective subculture have typical small colonies containing piliated bacteria. On nonselective subculture, larger colonies containing nonpiliated gonococci are also formed. Opaque and transparent variants of both the small and large colony types also occur; the opaque colonies are associated with the presence of a surface-exposed protein, Opa.

Antigenic Structure

N gonorrhoeae is antigenically heterogeneous and capable of changing its surface structures in vitro—and presumably in vivo—to avoid host defenses. Surface structures include the following.

A. Pili (Fimbriae)

Pili are the hairlike appendages that extend up to several micrometers from the gonococcal surface. They enhance attachment to host cells and resistance to phagocytosis. They are made up of stacked pilin proteins (molecular weight [MW], 17–21 kDa). The amino terminal of the pilin molecule, which contains a high percentage of hydrophobic amino acids, is conserved. The amino acid sequence near the midportion of the molecule also is conserved; this portion of the molecule serves in attachment to host cells and is less prominent in the immune response. The amino acid sequence near the carboxyl terminal is highly variable; this portion of the molecule is most prominent in the immune response. The pilins of almost all strains of N gonorrhoeae are antigenically different, and a single strain can make many antigenically distinct forms of pilin.

B. Por

Por protein extends through the gonococcal cell membrane. It forms pores in the surface through which some nutrients enter the cell. Por proteins may impact intracellular killing of gonococci within neutrophils by preventing phagosome–lysosome fusion. In addition, variable resistance of gonococci to killing by normal human serum depends on whether Por protein selectively binds to complement components C3b and C4b. The MW of Por varies from 32 to 36 kDa. Each strain of gonococcus expresses only one of two types of Por, but the Por of different strains is antigenically different. Serologic typing of Por by agglutination reactions with monoclonal antibodies was a useful method for studying the epidemiology of N gonorrhoeae. However, this method has been replaced by genotypic methods such as pulsed-field gel electrophoresis, Opa typing, and DNA sequencing.

C. Opa Proteins

These proteins function in adhesion of gonococci within colonies and in attachment of gonococci to host cell receptors such as heparin-related compounds and CD66 or carcinoembryonic antigen–related cell adhesion molecules. One portion of the Opa molecule is in the gonococcal outer membrane, and the rest is exposed on the surface. The MW of Opa ranges from 20 to 28 kDa. A strain of gonococcus can express no, one, two, or occasionally three types of Opa, but each strain has 11–12 genes for different Opas. PCR of the opa genes followed by restriction endonuclease digestion, and analysis of subsequent fragments by gel electrophoresis is a useful method of strain typing performed by reference laboratories.

D. Rmp (Protein III)

This protein (MW, 30–31 kDa) is antigenically conserved in all gonococci. It is a reduction-modifiable protein (Rmp) and changes its apparent MW when in a reduced state. It associates with Por in the formation of pores in the cell surface.

E. Lipooligosaccharide

In contrast to the enteric gram-negative rods (see Chapters 2 and 15), gonococcal lipopolysaccharide (LPS) does not have long O-antigen side chains and is called a lipooligosaccharide (LOS). Its MW is 3–7 kDa. Gonococci can express more than one antigenically different LOS chain simultaneously. Toxicity in gonococcal infections is largely attributable to the endotoxic effects of LOS. Specifically, in the fallopian tube explant model, LOS causes ciliary loss and mucosal cell death.

In a form of molecular mimicry, gonococci make LOS molecules that structurally resemble human cell membrane glycosphingolipids. A structure is depicted in Figure 20-3. The gonococcal LOS and the human glycosphingolipid of the same structural class react with the same monoclonal antibody, indicating the molecular mimicry. The presence on the gonococcal surface of the same surface structures as human cells helps gonococci evade immune recognition.

The terminal galactose of human glycosphingolipids is often conjugated with sialic acid. Sialic acid is a nine-carbon, 5-N-acetylated ketulosonic acid also called N-acetylneuraminic acid (NANA). Gonococci do not make sialic acid but do make a sialyltransferase that functions to take NANA from the human nucleotide sugar cytidine 5′-monophospho-N-acetylneuraminic acid (CMPNANA) and place the NANA on the terminal galactose of a gonococcal acceptor LOS. This sialylation affects the pathogenesis of gonococcal infection. It makes the gonococci resistant to killing by the human antibody–complement system and interferes with gonococcal binding to receptors on phagocytic cells.

N meningitidis and Haemophilus influenzae make many but not all of the same LOS structures as N gonorrhoeae. The biology of the LOS for the three species and for some of the nonpathogenic Neisseria species is similar. Four of the various serogroups of N meningitidis make different sialic acid capsules (see later discussion), indicating that they also have biosynthetic pathways different from those of gonococci. These four serogroups sialylate their LOS using sialic acid from their endogenous pools.

F. Other Proteins

Several antigenically constant proteins of gonococci have poorly defined roles in pathogenesis. Lip (H8) is a surface-exposed protein that is heat modifiable like Opa. The Fbp (ferric-binding protein), similar in MW to Por, is expressed when the available iron supply is limited, such as in human infection. Gonococci elaborate an IgA1 protease that splits and inactivates IgA1, a major mucosal immunoglobulin of humans. Meningococci, H influenzae, and Streptococcus pneumoniae elaborate similar IgA1 proteases.

Genetics and Antigenic Heterogeneity

Gonococci have evolved mechanisms for frequently switching from one antigenic form (pilin, Opa, or LPS) to another antigenic form of the same molecule. This switching takes place in one in every 10^2.5–10³ gonococci, an extremely rapid rate of change for bacteria. Because pilin, Opa, and LPS are surface-exposed antigens on gonococci, they are important in the immune response to infection. The molecules’ rapid switching from one antigenic form to another helps the gonococci elude the host immune system.

The switching mechanism for pilin, which has been the most thoroughly studied, is different from the mechanism for Opa.

Gonococci have multiple genes that code for pilin, but only one gene is inserted into the expression site. Gonococci can remove all or part of this pilin gene and replace it with all or part of another pilin gene. This mechanism allows gonococci to express many antigenically different pilin molecules over time.

The switching mechanism of Opa involves, at least in part, the addition or removal from the DNA of one or more of the pentameric coding repeats preceding the sequence that codes for the structural Opa gene. The switching mechanism of LPS is unknown.

Gonococci contain several plasmids; 95% of strains have a small, “cryptic” plasmid (MW, 2.6 mDa) of unknown function. Two other plasmids (MW, 3.4 and 4.7 mDa) contain genes that code for TEM-1 type (penicillinases) β-lactamases, which cause resistance to penicillin. These plasmids are transmissible by conjugation among gonococci; they are similar to a plasmid found in penicillinase-producing Haemophilus species and may have been acquired from Haemophilus or other gram-negative organisms. About 5–20% of gonococci contain a plasmid (MW, 24.5 × 10⁶ kDa) with the genes that code for conjugation; the incidence is highest in geographic areas where penicillinase-producing gonococci are most common. High-level tetracycline resistance (minimum inhibitory concentrations [MICs] of ≥16 mg/L) has developed in gonococci by the insertion of a streptococcal gene tetM coding for tetracycline resistance into the conjugative plasmid.

Pathogenesis, Pathology, and Clinical Findings

Gonococci exhibit several morphologic types of colonies (see earlier discussion), but only piliated bacteria appear to be virulent. Opa protein expression varies depending on the type of infection. Gonococci that form opaque colonies are isolated from men with symptomatic urethritis and from uterine cervical cultures at midcycle. Gonococci that form transparent colonies are frequently isolated from men with asymptomatic urethral infection, from menstruating women, and from patients with invasive forms of gonorrhea, including salpingitis and disseminated infection. Antigenic variation of surface proteins during infection allows the organism to circumvent host immune response.

Gonococci attack mucous membranes of the genitourinary tract, eye, rectum, and throat, producing acute suppuration that may lead to tissue invasion; this is followed by chronic inflammation and fibrosis. Men usually have urethritis, with yellow, creamy pus and painful urination. The process may extend to the epididymis. As suppuration subsides in untreated infection, fibrosis occurs, sometimes leading to urethral strictures. Urethral infection in men can be asymptomatic. In women, the primary infection is in the endocervix and extends to the urethra and vagina, giving rise to mucopurulent discharge. It may then progress to the uterine tubes, causing salpingitis, fibrosis, and obliteration of the tubes. Infertility occurs in 20% of women with gonococcal salpingitis. Chronic gonococcal cervicitis and proctitis are often asymptomatic.

Gonococcal bacteremia leads to skin lesions (especially hemorrhagic papules and pustules) on the hands, forearms, feet, and legs and to tenosynovitis and suppurative arthritis, usually of the knees, ankles, and wrists. Gonococci can be cultured from blood or joint fluid of only 30% of patients with gonococcal arthritis. Gonococcal endocarditis is an uncommon but severe infection. Gonococci sometimes cause meningitis and eye infections in adults; these have manifestations similar to those caused by meningococci. Complement deficiency is frequently found in patients with gonococcal bacteremia. Patients with bacteremia, especially if recurrent, should be tested for total hemolytic complement activity.

Gonococcal ophthalmia neonatorum, an infection of the eye in newborns, is acquired during passage through an infected birth canal. The initial conjunctivitis rapidly progresses and, if untreated, results in blindness. To prevent gonococcal ophthalmia neonatorum, instillation of tetracycline, erythromycin, or silver nitrate into the conjunctival sac of newborns is compulsory in the United States.

Gonococci that produce localized infection are often serum sensitive (ie, killed by antibody and complement).

Diagnostic Laboratory Tests

A. Specimens

Pus and secretions are taken from the urethra, cervix, rectum, conjunctiva, throat, or synovial fluid for culture and smear. Blood culture is necessary in systemic illness, but a special culture system is helpful because gonococci (and meningococci) may be susceptible to the polyanethol sulfonate present in standard blood culture media. Proprietary swabs may be required for diagnostic molecular assays. Clinicians should check with clinical laboratories regarding the appropriate collection devices for the assays used in a particular institution.

B. Smears

Gram-stained smears of urethral or endocervical exudates reveal many diplococci within pus cells. These give a presumptive diagnosis. Stained smears of the urethral exudate from men have a sensitivity of about 90% and a specificity of 99%. Stained smears of endocervical exudates have a sensitivity of about 50% and a specificity of about 95% when examined by an experienced microscopist. Additional diagnostic testing of urethral exudates from men is not necessary when the stain result is positive, but nucleic acid amplification tests (NAATs) or cultures should be done for women. Stained smears of conjunctival exudates can also be diagnostic, but those of specimens from the throat or rectum are generally not helpful.

C. Culture

Immediately after collection, pus or mucus is streaked on enriched selective medium (eg, modified Thayer-Martin medium [MTM]) and incubated in an atmosphere containing 5% CO₂ (candle extinction jar) at 37°C. To avoid overgrowth by contaminants, the selective medium contains antimicrobial drugs (eg, vancomycin, 3 μg/mL; colistin, 7.5 μg/mL; amphotericin B, 1 μg/mL; and trimethoprim, 3 μg/mL). If immediate incubation is not possible, the specimen should be placed in a CO₂-containing transport-culture system. Forty-eight hours after culture, the organisms can be quickly identified by their appearance on a Gram-stained smear; by oxidase positivity; and by coagglutination, immunofluorescence staining, or other laboratory tests. The species of subcultured bacteria may be determined by oxidation of specific carbohydrates (see Table 20-1). Matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF MS) has potential to provide rapid (same-day) identification of cultured isolates. The gonococcal isolates from anatomic sites other than the genital tract or from children should be identified as to species using two different confirmatory tests because of the legal and social implications of a positive culture result. Most laboratories have abandoned culture in favor of NAATs. Because of this, it may be difficult to monitor for increasing multidrug resistance (see discussion below). Culture should be considered in a patient who appears to have failed standard treatment.

D. Nucleic Acid Amplification Tests

Several Food and Drug Administration–cleared nucleic acid amplification assays are available for direct detection of N gonorrhoeae in genitourinary specimens, and these are the preferred tests from these sources. In general, these assays have excellent sensitivity and specificity in symptomatic, high-prevalence populations. Advantages include better detection, more rapid results, and the ability to use urine as a specimen source. Disadvantages include poor specificity of some assays because of cross-reactivity with nongonococcal Neisseria species. Some of these assays are not approved for use in the diagnosis of extragenital gonococcal infections or for infection in children. NAATs are not recommended as tests of cure because nucleic acid may persist in patient specimens for up to 3 weeks after successful treatment. Patients who are believed to have failed treatment are best reevaluated using culture so that the organism can be tested for resistance (see discussion below under Treatment).

E. Serology

Serum and genital fluid contain IgG and IgA antibodies against gonococcal pili, outer membrane proteins, and LPS. Some IgM of human sera is bactericidal for gonococci in vitro.

In infected individuals, antibodies to gonococcal pili and outer membrane proteins can be detected by immunoblotting, radioimmunoassay, and enzyme-linked immunosorbent assay (ELISA) tests. However, these tests are not useful as diagnostic aids for several reasons, including gonococcal antigenic heterogeneity, the delay in development of antibodies in acute infection, and a high background level of antibodies in the sexually active population.

Immunity

Repeated gonococcal infections are common. Protective immunity to reinfection does not appear to develop as part of the disease process, because of the antigenic variety of gonococci. Although antibodies can be demonstrated, including the IgA and IgG on mucosal surfaces, they either are highly strain specific or have little protective ability.

Treatment

Since the development and widespread use of penicillin, gonococcal resistance to penicillin has gradually risen, owing to the selection of chromosomal mutants and to increased prevalence of penicillinase-producing N gonorrhoeae (PPNG) (see earlier discussion). Chromosomally mediated resistance to tetracycline (MIC ≥2 μg/mL) is common. High-level resistance to tetracycline (MIC ≥ 32 μg/mL) also occurs. Spectinomycin resistance as well as resistance to fluoroquinolones has been noted. Single-dose fluoroquinolone treatment was recommended for treatment of gonococcal infections from 1993 until 2006. Since 2006, rates of quinolone resistance among gonococcal isolates have exceeded 5% in men who have sex with men and in heterosexual men. Because of the problems with antimicrobial resistance in N gonorrhoeae, the Centers for Disease Control and Prevention (CDC) recommended that patients with uncomplicated genital or rectal infections be treated with ceftriaxone (250 mg) given intramuscularly as a single dose or 400 mg of oral cefixime as a single dose. Additional therapy with 1 g of azithromycin orally in a single dose or with 100 mg of doxycycline orally twice a day for 7 days is recommended for possible concomitant chlamydial infections. Unfortunately, new data from CDC’s Gonococcal Isolate Surveillance Project (GISP) have noted an increase in the percentage of isolates exhibiting elevated MICs to both oral cefixime and ceftriaxone. This observation, combined with reports of cefixime treatment failures in other countries, has resulted in revised treatment guidelines. Since ceftriaxone is more potent than cefixime, the CDC no longer recommends cefixime as an effective treatment. Injectable ceftriaxone 250 mg IM once plus either azithromycin or doxycycline as written above is recommended for treatment of uncomplicated urethritis, cervicitis, and proctitis. Azithromycin has been found to be safe and effective in pregnant women, but doxycycline is contraindicated. Modifications of these therapies are recommended for other types of N gonorrhoeae infection. See the CDC’s website for the update to the 2010 treatment guidelines (http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6131a3.htm?s_cid=mm6131a3_w).

Because other sexually transmitted diseases may have been acquired at the same time as gonorrhea, steps must also be taken to diagnose and treat these diseases (see discussions of chlamydiae, syphilis, and so on).

Epidemiology, Prevention, and Control

Gonorrhea is worldwide in distribution. In the United States, its incidence rose steadily from 1955 until the late 1970s, when the incidence was between 400 and 500 cases per 100,000 population. Between 1975 and 1997, there was a 74% decline in the rate of reported gonococcal infections. Thereafter, the rates plateaued for 10 years and decreased from 2006 to 2009, but since 2009 rates have once again increased slightly each year. Gonorrhea is exclusively transmitted by sexual contact, often by women and men with asymptomatic infections. The infectivity of the organism is such that the chance of acquiring infection from a single exposure to an infected sexual partner is 20–30% for men and even greater for women. The infection rate can be reduced by avoiding multiple sexual partners, rapidly eradicating gonococci from infected individuals by means of early diagnosis and treatment, and finding cases and contacts through education and screening of populations at high risk. Mechanical prophylaxis (condoms) provides partial protection. Chemoprophylaxis is of limited value because of the rise in antibiotic resistance of the gonococcus.

Gonococcal ophthalmia neonatorum is prevented by local application of 0.5% erythromycin ophthalmic ointment or 1% tetracycline ointment to the conjunctiva of newborns. Although instillation of silver nitrate solution is also effective and is the classic method for preventing ophthalmia neonatorum, silver nitrate is difficult to store and causes conjunctival irritation; its use has largely been replaced by use of erythromycin or tetracycline ointment.

Antigenic Structure

At least 13 serogroups of meningococci have been identified by immunologic specificity of capsular polysaccharides. The most important serogroups associated with disease in humans are A, B, C, X, Y, and W-135. In contrast to the other capsular serogroups in which the capsule is composed of sialic acid moieties, the group A polysaccharide is a polymer of N-acetyl-mannosamine-1-phosphate. Incorporation of human sialic acid derivatives such as NANA into the meningococcal capsules allows the organism to be overlooked by the host immune system (often referred to as “molecular mimicry”). Meningococcal antigens are found in blood and cerebrospinal fluid of patients with active disease. Outbreaks and sporadic cases in the Western hemisphere in the past decade have been caused mainly by groups B, C, W-135, and Y; outbreaks in southern Finland and São Paulo, Brazil, were caused by groups B and C; outbreaks in New Zealand have been caused by a particular B strain; and those in Africa were mainly caused by group A. Group C and, especially, group A are associated with epidemic disease.

The outer membrane of N meningitidis consists of proteins and LPS that play major roles in organism virulence. There are two porin proteins (Por A and Por B) that are important in controlling nutrient diffusion into the organism and also interact with host cells. These porins have been targets of interest in vaccine development. The opacity proteins (Opa) are comparable to Opa of the gonococci and play a role in attachment. Meningococci are piliated and these structures initiate binding to nasopharyngeal epithelial cells and other host cells such as endothelium and erythrocytes. The lipid A disaccharide of meningococcal LPS is responsible for many of the toxic effects found in meningococcal disease. The highest levels of endotoxin measured in sepsis have been found in patients with meningococcemia (50- to 100-fold greater than with other gram-negative infections). Collectively, these structures and proteins are responsible for the devastating clinical features so characteristic of meningococcal infections.

Pathogenesis, Pathology, and Clinical Findings

Humans are the only natural hosts for whom meningococci are pathogenic. The nasopharynx is the portal of entry. There, the organisms attach to epithelial cells with the aid of pili; they may form part of the transient microbiota without producing symptoms. From the nasopharynx, organisms may reach the bloodstream, producing bacteremia; the symptoms may be similar to those of an upper respiratory tract infection. Fulminant meningococcemia is more severe, with a high fever and a hemorrhagic rash; the patient may have disseminated intravascular coagulation and circulatory collapse (Waterhouse-Friderichsen syndrome).

Meningitis is the most common complication of meningococcemia. It usually begins suddenly with an intense headache, vomiting, and stiff neck and progresses to coma within a few hours.

During meningococcemia, there is thrombosis of many small blood vessels in many organs, with perivascular infiltration and petechial hemorrhages. There may be interstitial myocarditis, arthritis, and skin lesions. In meningitis, the meninges are acutely inflamed, with thrombosis of blood vessels and exudation of polymorphonuclear leukocytes, so that the surface of the brain is covered with a thick purulent exudate.

It is not known what transforms an asymptomatic infection of the nasopharynx into meningococcemia and meningitis, but this can be prevented by specific bactericidal serum antibodies against the infecting serotype. Neisseria bacteremia is favored by the absence of bactericidal antibody (IgM and IgG), inhibition of serum bactericidal action by a blocking IgA antibody, or a complement component deficiency (C5, C6, C7, or C8). Meningococci are readily phagocytosed in the presence of a specific opsonin.

Diagnostic Laboratory Tests

A. Specimens

Specimens of blood are taken for culture, and specimens of spinal fluid are taken for smear, culture, and even some laboratories molecular testing. Nasopharyngeal swab cultures are suitable for carrier surveys. Puncture material from petechiae may be taken for smear and culture.

B. Smears

Gram-stained smears of the sediment of centrifuged spinal fluid or of petechial aspirate often show typical neisseriae within polymorphonuclear leukocytes or extracellularly.

C. Culture

Culture media without sodium polyanethol sulfonate are helpful in culturing blood specimens. Cerebrospinal fluid specimens are plated on chocolate agar and incubated at 37°C in an atmosphere of 5% CO₂. A MTM with antibiotics (vancomycin, colistin, amphotericin) favors the growth of neisseriae, inhibits many other bacteria, and is used for nasopharyngeal cultures. Presumptive colonies of neisseriae on solid media, particularly in mixed culture, can be identified by Gram stain and the oxidase test. Spinal fluid and blood generally yield pure cultures that can be further identified by carbohydrate oxidative reactions (see Table 20-1) and agglutination with type-specific or polyvalent serum.

D. Serology

Antibodies to meningococcal polysaccharides can be measured by latex agglutination or hemagglutination tests or by their bactericidal activity. These tests are done only in reference laboratories.

Immunity

Immunity to meningococcal infection is associated with the presence of specific, complement-dependent, bactericidal antibodies in the serum. These antibodies develop after subclinical infections with different strains or injection of antigens and are group specific, type specific, or both. The immunizing antigens for groups A, C, Y, and W-135 are the capsular polysaccharides. For group B, a specific antigen suitable for use as a vaccine has not been defined; however, group B vaccines with mixtures of antigens have been used in many parts of the world. Recently, one such vaccine 4CMenB (Bexsero^®) was licensed in the European Union. Currently, there are three vaccines against serogroups A, C, Y, and W-135 and one that contains only C and Y available in the United States. A polysaccharide tetravalent vaccine (Menomune^®, Sanofi Pasteur) in which each dose consists of four purified bacterial capsular polysaccharides is poorly immunogenic in children younger than age 18 months, does not confer long-lasting immunity, and does not cause a sustainable reduction in nasopharyngeal carriage. This is approved as a single dose for individuals ≥ 2 years. A tetravalent conjugate vaccine approved in 2005 (Menactra™, Sanofi Pasteur) is licensed for use in persons 9 months to 55 years of age. It contains capsular polysaccharide conjugated to diphtheria toxoid. In children aged 9–23 months, two doses are required. Menveo (Novartis) is another tetravalent conjugate vaccine in which A, C, Y, W135 oligosaccharide is conjugated to diphtheria CRM197. This vaccine is approved for use in individuals 2–55 years of age. The Hib-MenCy-TT conjugate vaccine (GlaxoSmithKline) is a four-dose series vaccine approved for children 6 weeks to 18 months old. A quadrivalent meningococcal vaccine in which tetanus toxoid is the conjugate protein (MenACWY-tt; Nimenrix^®) is available in Europe. The advantage of the conjugate vaccines is that a T cell–dependent response to vaccine is induced. This enhances primary response among infants and substantially reduces asymptomatic carriage.

Routine vaccination of all young adolescents (ages 11–12 years) before high school with a booster dose at age 16 years using an approved conjugate vaccine is now recommended. Vaccination is also recommended for persons 2 months of age or older who are among the following at-risk groups: persons with functional or surgical asplenia, and persons with complement deficiencies. Persons aged 9 months or older who are travelers to or residents of highly endemic areas (eg, sub-Saharan Africa), “closed populations” such as college freshman living in dorms and the military, populations experiencing a community outbreak, and clinical laboratory workers (microbiologists) are other at-risk groups who should routinely be vaccinated.

Treatment

Penicillin G is the drug of choice for treating patients with meningococcal disease. Either chloramphenicol or a third-generation cephalosporin such as cefotaxime or ceftriaxone is used in persons who are allergic to penicillins.

Epidemiology, Prevention, and Control

Meningococcal meningitis occurs in epidemic waves (eg, in military encampments, in religious pilgrims, and in sub-Saharan Africa, the so-called “meningitis belt”); and a smaller number of sporadic interepidemic cases. Serogroup A is responsible for the majority of outbreaks in sub-Saharan Africa, whereas serogroup B is most often the cause of sporadic infections. About 5–30% of the normal population may harbor meningococci (often nontypeable isolates) in the nasopharynx during interepidemic periods. During epidemics, the carrier rate goes up to 70–80%. A rise in the number of cases is preceded by an increased number of respiratory carriers. Treatment with oral penicillin does not eradicate the carrier state. Rifampin, 600 mg orally for adults, 5 mg/kg for children < 1 month, or 10 mg/kg for children 1 month or older twice daily for 2 days, is recommended as chemoprophylaxis for household and other close contacts following exposure to an index case. Ciprofloxacin in adults, 500 mg as a single dose, and ceftriaxone in children < 15 years, 125 mg IM as a single dose, are alternative agents. Clinical cases of meningitis present only a negligible source of infection, and isolation therefore has only limited usefulness. More important is the reduction of personal contacts in a population with a high carrier rate. This is accomplished by avoidance of crowding or administration of vaccines as discussed.

N lactamica very rarely causes disease but is important because it grows in the selective media (eg, modified MTM) used for cultures of gonococci and meningococci from clinical specimens. N lactamica can be cultured from the nasopharynx of 3–40% of persons and most often is found in children. Unlike the other neisseriae, it ferments lactose.

N sicca, N subflava, N cinerea, Neisseria mucosa, and N flavescens are also members of the normal microbiota of the respiratory tract, particularly the nasopharynx, and very rarely produce disease. N cinerea sometimes resembles N gonorrhoeae because of its morphology and positive hydroxyprolyl aminopeptidase reaction.

M catarrhalis was previously named Branhamella catarrhalis and before that Neisseria catarrhalis. It is a member of the normal microbiota in 40% to 50% of healthy school children. M catarrhalis causes bronchitis, pneumonia, sinusitis, otitis media, and conjunctivitis. It is also of concern as a cause of infection in immunocompromised patients. Most strains of M catarrhalis from clinically significant infections produce β-lactamase. M catarrhalis can be differentiated from the neisseriae by its lack of carbohydrate fermentation and by its production of DNase. It produces butyrate esterase, which forms the basis for rapid fluorometric tests for identification.

• The genus Neisseria consists of two major pathogens, N gonorrhoeae and N meningitidis; both of them have elaborated factors that facilitate disease in otherwise healthy people. The remaining species constitute part of the normal human microbiota of the respiratory tract and may play a role in localized infections.

• Members of this genus are gram-negative diplococci that vary in their growth requirements. N gonorrhoeae is very fastidious, and selective enriched media containing antibiotics, amino acids, and so on are used to recover the organism in clinical cultures. The other species are less fastidious and grow on routine laboratory media.

• N gonorrhoeae causes the sexually transmitted disease gonorrhea and is characterized by purulent cervicitis in women and purulent urethral discharge in men. Infants born to women infected at the time of delivery may develop purulent conjunctivitis.

• Diagnosis is made primarily by NAATs; treatment consists of intramuscular ceftriaxone plus an agent such as azithromycin or doxycycline to treat concomitant Chlamydia infections.

• N meningitidis is the cause of endemic and epidemic meningitis. Its major virulence factor is the thick polysaccharide capsule. There are approximately 13 capsular types, of which the most common causes of disease are A, B, C, X, Y, and W-135.

• Meningococcal meningitis is a serious infection that carries a high morbidity and is often associated with sepsis because of its potent LOS. Penicillin is the drug of choice.

• Diagnosis is made by culturing the cerebrospinal fluid on chocolate agar incubated at 37°C in CO₂.

• Prevention consists of immunization with one of two conjugate vaccines (routinely recommended for children 11–12 years of age) or the polysaccharide vaccine.