ACP medicine, 3rd Edition

Infectious Disease

Infections Due to Neisseria

Jeanne M. Marrazzo M.D., M.P.H.1

1Assistant Professor of Medicine, University of Washington School of Medicine

The author has no commercial relationships with manufacturers of products or providers of services discussed in this subsection.

January 2003

Infections caused by Neisseria species are among the most frequently encountered and potentially dangerous diseases. The two major species of concern are N. meningitidis and N. gonorrhoeae. Both are gram-negative cocci that reside primarily in polymorphonuclear white blood cells and tend to cluster in pairs [see Figure 1]. No nonhuman reservoir exists for either organism. Although there is some overlap in the clinical syndromes these two species elicit, they are commonly known for distinctly different presentations.

 

Figure 1. Urethral Secretions showing N. Gonorrhoeae

Gram stain of urethral secretions showing abundant N. gonorrhoeae as gram-negative diplococci within polymorphonuclear cells.

Infections Caused by Neisseria meningitidis

The most clinically relevant classification scheme for N. meningitidis utilizes the organism's capsular polysaccharides and includes at least 13 serogroups. The most common of these are A, B, C, X, Y, L, and W135.1 In addition to serogroup, the organism can be classified by class 1 outer-membrane proteins (OMP) (serosubtype), class 2 or 3 OMP (serotype), and lipo-oligosaccharide (immunotype).

Invasive disease caused by N. meningitidis is a significant source of morbidity and mortality worldwide. Important trends include increased recognition of the Y serogroup's role in outbreaks, consideration of college freshmen as candidates for vaccination, and the relative increase of N. meningitidis as a pathogen in children as the success of immunization against Haemophilus influenzae type b is increasingly realized.

EPIDEMIOLOGY AND TRANSMISSION

  1. meningitidisis most commonly found in the setting of asymptomatic nasopharyngeal carriage. The prevalence of nasopharyngeal colonization in the United States is estimated at 5% to 10%.2Duration of colonization varies from transient (days) to as long as 2 years, with a median of 9 to 10 months. Development of humoral immunity to the colonizing strain of the organism is common and may last at least 4 to 6 months after exposure.

Transmission results from direct transfer of respiratory or oral secretions and requires prolonged intimate contact. Consequently, habitation in very close quarters (e.g., military barracks, correctional facilities, and college dormitories) can facilitate colonization, the prevalence of which can reach 20% to 40% during outbreaks.3 Facilitation of transmission within close quarters is also reflected by seasonal patterns in invasive infection. Although disease occurs year-round, the incidence peaks in late winter and early spring. Transmission has also been documented through prolonged exposure to an infected person on an airplane and in laboratory technicians working with isolates on open laboratory benches.4,5

Despite longstanding availability of antibiotics and meningococcal vaccine, most areas of the world continue to have stable rates of endemic disease. After Streptococcus pneumoniae, N. meningitidis is the most common cause of bacterial meningitis worldwide, causing an estimated 25% of cases.6 In the United States, laboratory-based surveillance for invasive meningococcal disease from 1992 to 1996 revealed an average annual incidence of 1.1 cases per 100,000 population (approximately 2,454 cases a year).2,6,7 Incidence was highest in infants younger than 1 year, with a rate of 15.9/100,000 for children 4 to 5 months of age. The serogroup associated with the most cases of invasive disease was serogroup C (35%); however, significant geographic variation was seen, and the incidence of disease from serogroup Y increased during the study period.7 For reasons that are unclear, rates of invasive meningococcal disease in the United States are higher in blacks than in nonblacks.

The risk of invasive meningococcal infection in college students has been summarized by the Centers for Disease Control and Prevention (CDC),8 which initiated surveillance in this group in 1998. Whereas the incidence in undergraduates overall was lower than that in persons 18 to 23 years of age who were not enrolled in college, rates were relatively high in the approximately 590,000 freshmen who lived in dormitories (4.6/100,000).

Sporadic outbreaks of invasive meningococcal disease also continue to occur in sub-Saharan Africa, in an area extending from Senegal in the west to Ethiopia in the east, known as the meningitis belt. Outbreaks caused primarily by serogroup A occur there during the dry season, from December to June. However, serogroups B and C have caused large epidemics elsewhere, including the United States.7

PATHOGENESIS AND IMMUNITY

The cascade of events from exposure to colonization and from invasion to specific manifestations of clinical disease is complex. Most persons who develop invasive meningococcal disease do so after recent colonization.1 Concomitant upper respiratory viral infection, cigarette smoking, underlying chronic illness, and preceding Mycoplasma infection may facilitate meningococcal infection and colonization. Colonization requires attachment to nonciliated columnar mucosal cells of the nasopharynx. Meningococci secrete proteases that cleave IgA, which may disable a major mucosal defense mechanism; how this mechanism contributes to pathogenesis is unclear, however. Endocytosis and intracellular transport of meningococci-laden vacuoles mediate the organisms' passage to the submucosa.

Immunity to meningococcus involves interactions at the nasopharyngeal mucosa, innate immune mechanisms, and acquired antibody.9,10The importance of antibody is highlighted by several findings. Natural immunity is acquired after, and boosted by, meningococcal colonization of the nasopharynx. Immunity correlates with bactericidal antibody levels in serum, and the age-specific attack rate of meningococcal disease is reciprocally related to the presence of serogroup-specific antibodies.9 Further, hypogammaglobulinemia is a risk factor for invasive disease. In military recruits, risk of disease is highest in the absence of bactericidal activity against the prevalent pathogenic strain.11 Specific antibody directly binds the meningococcus and activates complement-mediated phagocytosis.

Both pathways of the complement system—classic and alternative—appear critical in controlling meningococcal infection.9 Persons with deficiencies in the terminal complement system (C5, C6, C7, C8, or C9) develop antibody to meningococci, but the rates of meningococcal infection in these individuals are 1,400-fold to 10,000-fold higher than in the general population.12 Approximately 50% of affected persons have at least one episode of meningococcal infection, and 20% to 25% have more than one episode. Of note, infections in persons with complement deficiency often involve unusual serogroups and are less severe. Persons with deficiencies of properdin (an alternative-pathway component) or factor D are also at increased risk for meningococcal disease, with a case-fatality rate of over 50%. Recurrent meningococcal disease should prompt screening for complement deficiencies,13 which involves testing the serum for hemolytic whole-complement activity.

Coagulopathy and microvascular thrombosis are hallmarks of meningococcal sepsis. The most visible manifestation of these processes is purpura fulminans [see Figure 2a and 2b]. Dysfunction of the activation pathway of protein C appears to play a key role in these thrombotic events. When activated by its binding to thrombomodulin and the endothelial protein C receptor, protein C normally functions to keep thrombin's procoagulant properties in check. In children with purpuric lesions from meningococcal sepsis, endothelial protein C activation is impaired.14

 

Figure 2a. Rash of Purpura Fulminans

(a) The rash of purpura fulminans, seen here with petechiae as well as larger, coalescent hemorrhagic lesions, in a patient with meningococcal sepsis and meningitis caused by serogroup B.
 

Figure 2b. Close view of Petechiae

(b) Closer view of petechiae, some of which have coalesced into purpuric and intracutaneous hemorrhagic lesions.

CLINICAL PRESENTATIONS

Meningococcal Bacteremia

Meningococcal bacteremia occurs across a spectrum of clinical presentations, ranging from an acute fulminant disease that is fatal within hours to asymptomatic infection. The presence of N. meningitidis in the blood is usually associated with severe illness. However, bacteremia may occasionally be found in persons who appear healthy or who have only mild systemic symptoms (usually fever and, sometimes, upper respiratory symptoms or rash resembling a viral exanthem).

Symptoms associated with so-called benign bacteremia usually resolve before the infection is identified by isolation of meningococcus from blood cultures. This syndrome differs from the so-called chronic meningococcemia associated with low-grade fever, rash, and polyarticular arthritis that can be confused with disseminated gonococcal infection (DGI).

The rash of chronic meningococcemia usually takes the form of a nonspecific maculopapular eruption, but it may be petechial. Unlike persons who experience recurrent meningococcal meningitis (see below), patients with chronic meningococcemia appear immunologically normal and are usually infected with typical serogroups. N. meningitidis should be considered in the evaluation of any patient with a chronic arthritis-dermatitis syndrome.

The most notorious presentations of meningococcal disease take two forms: meningococcemia and meningococcal sepsis. The two forms may occur simultaneously.

The term meningococcemia usually denotes bacteremia accompanied by signs of sepsis and frequently by the classic purpuric or petechial rash typical of this syndrome, which occurs in 75% of patients with this disease [see Figure 2a and 2b]. Although the rash of purpura fulminans is obvious, patients presenting early in the course of disease may have more subtle abnormalities of the skin and mucous membranes. These abnormalities include palpebral and conjunctival petechiae and lesions in areas subject to physical pressure, such as the waist and soles of the feet. Because these findings can herald the development of full-blown meningococcemia, they should be carefully sought in persons in whom this illness is a consideration; so that a thorough examination can be performed, the patient should be examined without clothes. Affected patients may also complain of intense, diffuse myalgias in the initial period of their illness. Evolution of individual petechiae to coalescence and eventual frank ecchymosis proceeds apace with the progression of the thrombocytopenia of disseminated intravascular coagulation (DIC).

Meningococcal sepsis is characterized by a rapid progression from general, nonspecific complaints that may resemble a viral illness to hypotension, multiorgan failure, and DIC. Despite the availability of antibiotics and advances in critical care, meningococcal sepsis still carries a mortality of up to 40%.2 Concomitant adrenal hemorrhage, known as the Waterhouse-Friderichsen syndrome, may also occur. Myocarditis has been noted on histopathologic examination in more than 70% of patients with fatal meningococcemia.15,16 Meningococcemia may also precipitate pericarditis, sometimes to the point of tamponade. The formation of arterial thrombi can result in peripheral gangrene.

Meningitis

Acute meningococcal meningitis results from hematogenous dissemination of the organism and is usually accompanied by classic signs of bacterial meningeal inflammation: fever, headache, and nuchal rigidity. Other findings typical of meningitis may occur, including photophobia, nausea, vomiting, focal neurologic signs, seizures, and progression to obtundation and coma.17 From 50% to 75% of patients have a petechial rash suggestive of meningococcemia.18 The cerebrospinal fluid is typically purulent, with numerous polymorphonuclear neutrophils (PMNs), low glucose (< 50 mg/dl, present in 75% of cases), and an elevated protein concentration. In contrast, the uncommon syndrome of recurrent meningococcal meningitis produces less severe clinical and CSF findings.

Bacteremic Pneumonia

Bacteremic pneumonia from N. meningitidis constituted 3% of cases of invasive meningococcal disease reported by Schuchat6 in 1997 and may be more commonly associated with serogroup Y isolates. However, meningococcal pneumonia probably occurs more frequently than is indicated by detection through positive blood cultures, and this disease has occurred in outbreaks. In a well-described outbreak involving 68 military recruits, most of the individuals had fever, rales, and pharyngitis.19 Although disease was multilobar in 40% of the patients, no deaths occurred. Diagnosis by sputum culture is problematic, given the potential confounding effect of upper airway colonization. Instead, most patients are diagnosed either at bronchoscopy or, if they have systemic infection, with positive cultures at nonpulmonary sites.

Other Meningococcal Infections

Uncommonly, N. meningitidis can cause syndromes for which N. gonorrhoeae is well known, including urethritis in men and cervicitis in women. One proposed mechanism of meningococcal genital infection is acquisition through orogenital sex, which may transmit nasopharyngeal colonizers to genital sites.20 These syndromes respond well to the antibiotics typically used for gonococcal genital infections (see below).21 Sex partners should be treated, but no further chemoprophylaxis (e.g., treatment of household contacts) is indicated.

Cases of N. meningitidis infecting numerous other body sites have been reported, including endocarditis, cellulitis, conjunctivitis, otitis media, epiglottitis, and arthritis.2,22,23

DIAGNOSIS

  1. meningitidisis a fastidious aerobic organism that grows best on chocolate agar and is distinguished from N. gonorrhoeaeby its ability to ferment both maltose and glucose. The bacteria can be isolated from blood in approximately 75% of persons with invasive meningococcal disease and from the CSF in approximately 46% to 94% of persons with meningitis.17 Sepsis occurs in an estimated 5% to 20% of persons with positive blood cultures. Gram stain of CSF remains a very useful means of detecting the meningococcus; however, its sensitivity is probably no higher than 50% to 70% and, like that of culture, is reduced by recent antibiotic use. Detection assays for polysaccharide antigens using countercurrent immunoelectrophoresis or latex agglutination are frequently applied to CSF. Their advantages include rapid turnaround time, high specificity, and ability to individuate serogroups. Their major disadvantage is relatively low sensitivity (meaning that false negatives occur), particularly if serogroup B is responsible; in addition, they are not reliable when used to detect antigen in urine or serum. The polymerase chain reaction (PCR) has been successfully applied to the detection of N. meningitidis, especially in the United Kingdom, but is not commercially available in the United States.24 Of note, the isolation of meningococci from upper respiratory secretions does not itself indicate meningococcal disease.

COMPLICATIONS AND PROGNOSIS

Meningococcal sepsis confers a mortality of up to 40%, and 11% to 19% of survivors suffer sequelae, including hearing loss, neurologic disability, and amputation because of peripheral gangrene.25 The case-fatality rate for all invasive meningococcal disease is estimated to be 11%, and it is significantly higher in the presence of bacteremia (17%) than with meningitis alone (3%). Mortality from N. meningitidis is most profound in children: in developed countries, invasive meningococcal disease is the leading cause of death in this age group. Among 295 adolescents and young adults with invasive meningococcal disease in Maryland during the 1990s, 22.5% of those 15 through 24 years of age died.26 Clearly, this disease continues to present a major challenge to physicians, communities, and the public health system.

DIFFERENTIAL DIAGNOSIS

In its earliest stage, the presentation of invasive meningococcal disease can be nonspecific, resembling a typical viral illness with fever and myalgias. Appearance of a rash should prompt consideration of common viral etiologies, including the enteroviruses. The presence of severe systemic illness should bring to mind Rocky Mountain spotted fever (RMSF), vasculitides (polyarteritis nodosa, Churg-Strauss syndrome, and anaphylactoid [Henoch-Schönlein] purpura), and toxic shock syndromes associated with staphylococcal, streptococcal, and, less commonly, clostridial infections. Less common infections that can present in similar fashion include epidemic typhus, infections caused byStreptobacillus moniliformis and Spirillum minus (rat-bite fever), gonococcemia, septicemia caused by H. influenzae type b, typhoid fever, and acute S. aureus endocarditis. Key pieces of information can help narrow the differential diagnosis. Tick-borne diseases such as RMSF usually occur within specific geographic confines and are generally associated with outdoor exposure to animal or insect vectors during the temperate months, principally in summer. Travel history is important in consideration of typhoid fever, as is information regarding the host's general immune status.

TREATMENT

Emergency Management

Infected patients should be isolated and droplet precautions observed until effective antimicrobial therapy has been given for at least 24 hours.27 Antibiotic therapy should be started as soon as possible. Earlier initiation of antibiotics has been demonstrated to favorably affect outcome in some, though not all, studies,28 but the disease is frequently so severe that reasonable measures to impact its early course should be undertaken.

Penicillin has constituted the mainstay of antibiotic therapy of meningococcal disease for several decades. Although β-lactamase-producing strains with high-level resistance (minimum inhibitory concentration [MIC] ≥ 250 µg/ml) exist, and strains with altered penicillin-binding proteins and intermediate resistance (MIC, 0.1 to 1.0 µg/ml) have been isolated clinically, treatment failures with penicillin have not been reported.29 Similarly, isolates with high-level resistance to chloramphenicol have been reported outside the United States. Given these data, meningococcal isolates from blood and CSF should be routinely evaluated for penicillin susceptibility at a reference laboratory.

Antibiotic Therapy

Until the presence of meningococcus is confirmed, the patient should receive empirical treatment for bacterial meningitis [see 7:XXXVI Bacterial Infections of the CSF]. Once N. meningitidis is identified in the CSF or blood, monotherapy with penicillin G (300,000 U/kg/day I.V., up to 24 million U/day) or ceftriaxone (50 mg/kg/day, up to 2 g) may be used. For persons who cannot tolerate penicillins or cephalosporins, chloramphenicol is an option; however, hematologic toxicity remains a concern. These antibiotics provide adequate CSF penetration, especially in the presence of meningeal inflammation. Treatment for 10 to 14 days is commonly recommended.29 Although fluoroquinolones provide excellent activity against N. meningitidis and achieve very good CSF levels, their role in the treatment of invasive meningococcal disease requires further study.

Adjunctive Therapy

Adjunctive therapy of meningococcal infection with corticosteroids has been a subject of intense debate. Steroid therapy has not been shown to improve outcomes associated with meningococcal disease and is therefore not recommended. Another strategy under pursuit is repletion of activated protein C, which is severely depleted in severe meningococcemia.30 One small open-label study showed that compared with predicted outcomes, there were reductions in morbidity and mortality from severe meningococcemia in patients treated with activated protein C.31 In a large, randomized, placebo-controlled study of patients with sepsis, recombinant protein C reduced mortality but also increased bleeding events.32 None of the patients in this study had sepsis from N. meningitidis. However, protein C depletion appears to be more severe in meningococcal disease than in related conditions that commonly cause sepsis, suggesting that further study is warranted. Recombinant protein C is commercially available, and its use in patients with sepsis from N. meningitidis should be considered.

PREVENTIVE THERAPY

Although outbreaks account for only 2% to 3% of all cases of meningococcal disease in the United States, prevention of the spread of disease carries a high priority. The risk of invasive disease in family members of persons with invasive meningococcal disease is increased by a factor of 400 to 800. Further, case clusters cause great alarm in the community. Consequently, assessment of the need for prophylaxis and coordination of its administration are critical steps in the management of invasive meningococcal disease. Assistance in carrying out these steps can be provided by the public health agencies to which cases of meningococcal disease must be reported (see below).

Prophylaxis is recommended for close contacts of infected persons [see Table 1]. Close contacts are defined as household members, day care center contacts, and anyone directly exposed to the patient's oral secretions (e.g., by kissing, by mouth-to-mouth resuscitation, during endotracheal intubation, or during endotracheal tube management by health care workers not wearing masks).33 The likelihood of contracting invasive disease from close contact is highest in the first few days after exposure; thus, prophylaxis should ideally be administered within 24 hours after identification of the index case and is unlikely to be of value if given beyond 14 days after onset of illness in the index case.34

Table 1 Chemoprophylaxis for Meningococcal Disease1

Drug

Dosage

Relative Efficacy

Comments

 

Children < 1 mo: 5 mg/kg p.o., q. 12 hr for 2 days

 

Not recommended for pregnant women, because it is teratogenic in animals; because reliability of oral contraceptives may be affected by rifampin, alternative contraceptive measures should be considered during its administration

Rifampin

Children ≥ 1 mo: 10 mg/kg p.o., q. 12 hr for 2 days

First choice

 

 

Adults: 600 mg q. 12 hr for 2 days

 

 

Ciprofloxacin

Adults: 500 mg p.o. once

Alternative

Not generally recommended for persons < 18 yr or for pregnant and lactating women, because it causes cartilage damage in immature laboratory animals; however, ciprofloxacin has been used extensively in children with cystic fibrosis without reported adverse outcomes; CDC recommends it for chemoprophylaxis in children when no acceptable alternative is available.

Ceftriaxone

Children < 15 yr: 125 mg I.M. once Adults: 250 mg I.M. once

Alternative

Indicated for pregnant women

 

Adults: 250 mg I.M. once

 

 

IMMUNIZATION

Vaccine

A quadrivalent polysaccharide vaccine for protection against N. meningitidis serogroups A, C, Y, and W-135 (Menomune) is currently available.35 It is administered subcutaneously as a single 0.5 ml dose, induces protective antibody within 7 to 10 days, and is generally well tolerated. No serious side effects have been reported. The vaccine may be administered to pregnant and lactating women, because no adverse events associated with immunization during pregnancy have been reported. An important consideration is that the vaccine does not provide protection against serogroup B infection, which causes over half of cases in infants younger than one year. Vaccine efficacy against serogroups A and C is estimated at 85% to 100% in older children and adults.36 Although protective immunity to serogroup A can be conferred in infants older than 3 months, immunity to serogroup C is difficult to attain in children younger than 1 year. No data are available on efficacy of the Y and W-135 polysaccharides in older children and adults, but these polysaccharides are safe and immunogenic. For all serogroups, limited data suggest that the duration of immunoprotection is probably no more than 3 years. Given this, as well as the difficulty of inducing an adequate immune response in infants, routine vaccination of infants is not recommended.

Several new meningococcal conjugate vaccines are under study for serogroups A, C, Y, and W-135, and they are likely to become available in the United States in the next few years.37 Unlike polysaccharide vaccines, they induce a stronger, longer-lasting immune response that can be boosted by subsequent doses. Serogroup C conjugate vaccines were introduced in the United Kingdom in 1999.

Recommendations for Vaccine Use

Vaccination is recommended for persons at increased risk, for prospective travelers, and for the control of outbreaks.

Persons at increased risk

Persons at increased inherent risk include military recruits and persons with terminal complement pathway deficiencies or functional or anatomic asplenia. Persons exposed routinely to N. meningitidis through occupational exposure (e.g., clinical or research laboratory personnel) should also consider vaccination.

Prospective travelers

Vaccination is recommended for travelers to areas endemic for invasive meningococcal disease, including parts of sub-Saharan Africa during peak periods of disease incidence (generally the dry season, from December to June). In addition, a large international outbreak in pilgrims to the Hajj in Saudi Arabia in 2001 prompted recommendations that travelers to this site also be immunized.38 Updated recommendations for this and other travel-related immunizations can be obtained at http://www.cdc.gov/travel.

Control of outbreaks

Vaccination may be considered as a means of controlling outbreaks caused by serogroups covered by the vaccine. The Advisory Committee on Immunization Practices (ACIP) recommends that mass vaccination of persons 2 years of age or older be considered when three cases of serogroup C meningococcal disease occur within a 3-month period in a community or organization (e.g., a school), with an incidence of 10 cases per 100,000 population or greater.39

Immunization of college freshmen, particularly those living in dormitories, deserves special mention. Although the rate of invasive infection in this group exceeds that of any age group other than children younger than 2 years, it is still below the threshold recommended for initiating meningococcal vaccination campaigns. Thus, ACIP recommends that health care providers and colleges inform students and their parents about the vaccine's availability and potential benefits.8 Many colleges recommend meningococcal vaccination to incoming freshmen, and some offer the vaccine through their student health service.

Requirements for Reporting Meningococcal Disease

Infection with N. meningitidis is reportable by law to most local and state health departments. Public health agencies will assist clinicians in the identification and treatment of exposed contacts; in the case of outbreaks, these agencies may institute other control measures. Physicians should not assume that clinical laboratories will execute reporting. Contact information for reporting communicable diseases can be found through state health departments, Web sites for which can be found at http://www.cdc.gov/mmwr/international/relres.html.

Infections Caused by Neisseria gonorrhoeae

Known primarily as a cause of sexually transmitted infections, N. gonorrhoeae remains an important cause of cervicitis, urethritis, proctitis, and pelvic inflammatory disease (PID) [see 7:XXII Sexually Transmitted Diseases]. No vaccine is available.

EPIDEMIOLOGY

An estimated 600,000 new cases of gonococcal infection occur in the United States each year.40 These cases are a mix of symptomatic infections, which occur mostly in men, and asymptomatic infections detected through routine testing, largely in women.

The incidence of gonorrhea declined steadily in the United States from 1978 through 1997, but rates increased in 1998 and have not declined since then. In particular, the incidence in adolescents, especially those in large cities, remains high; in addition, sustained outbreaks have occurred recently in men who have sex with men. In the United States in 2000, the highest reported rates of gonorrhea were in women 15 to 19 years of age (715.6 per 100,000 population) and in men 20 to 24 years of age (589.7 per 100,000 population).41 In 42 states, the incidence of gonorrhea in women remains above the objective of 19 new cases per 100,000 population from Healthy People 2010 (http://www.health.gov/healthypeople/document/html/objectives/25-02.htm), a set of health objectives for the United States developed through the Office of Disease Prevention and Health Promotion of the United States Department of Health and Human Services.

Rates of gonococcal infection have increased among men who report having sex with other men.42 In a surveillance project at six sexually transmitted disease clinics in five U.S. cities, positivity of urethral gonorrhea in this population was 21% for those who were HIV positive and 12% for those who were HIV negative. These findings have spurred some government agencies to recommend routine screening at least annually for gonorrhea in this population.43

Typing methods for the gonococcus are generally less clinically useful than for meningococcus and are used primarily to study gonococcal epidemiology. Most widely used are auxotyping, which classifies the organism on the basis of nutritional requirements, and protein I-serotyping, which is based on the stable antigenic diversity of its largest surface protein and further classifiable into different serovars by coagglutination assays. These two methods are combined into auxotype/serovar (A/S) classes for nomenclature of many strains (e.g., AHA/IA-1 denotes a strain that requires arginine, hypoxanthine, and uracil for growth and exhibits protein IA with a type 1 coagglutination pattern).21

PATHOGENESIS

The pathogenesis of N. gonorrhoeae has been closely studied in an experimental model using male human volunteers.44 Like N. meningitidis, the gonococcus possesses a protease that may be important in cleaving IgA at the mucosal surface. Columnar or cuboidal epithelium is the main target for attachment, which is mediated primarily by pili that protrude from the cell surface and by outer membrane proteins termed Opa proteins.45 Because they require iron for growth, gonococci possess transferrin receptors; they also contain lipo-oligosaccharide (LOS). The toxicity of LOS may be especially important in incapacitating the ciliary function of cells lining the fallopian tubes.45 Within 24 to 48 hours after attachment, the organism's penetration into submucosa elicits an intense neutrophilic inflammatory response. Submucosal microabscesses form, purulent exudate collects, and the affected epithelium sloughs, resulting in ready detection of intracellular gram-negative diplococci in neutrophils on Gram stain.

The role of systemic antibody in gonococcal infection is unclear, given that individuals may be infected multiple times. Gonococcal strains can differ in the clinical manifestations they induce. Some strains, such as AHU/IA-1, AHU/IA-2 and CU, have been associated with the uncommon finding of asymptomatic urethral infection in men and a higher incidence of DGI.46

CLINICAL PRESENTATIONS

  1. gonorrhoeaeis known primarily for its propensity to cause superficial mucosal infections that are transmitted through sexual contact. In men, these infections most commonly involve the urethra. After an incubation period of 1 to 14 days, 95% of men infected at this site experience dysuria and urethral discharge. The discharge is typically purulent but can be serous or seropurulent, especially early in the course of disease. Mild edema and erythema of the urethral meatus may be seen. If left untreated, infection usually resolves over the course of several weeks, and persistent asymptomatic carriage is thought to be unlikely. In some men with untreated urethral infection, infection may spread to cause epididymitis, prostatitis, seminal vesiculitis, and infections of the Cowper and Tyson glands.21The urethra may also be infected in women, but isolated urethral infection is unusual except in women who have undergone a hysterectomy. Urethral infection in women is less frequently symptomatic.

Endocervical Infection

In women, the most common site of infection is the endocervical canal, where N. gonorrhoeae may cause mucopurulent cervicitis (MPC). MPC presents as either mucopurulent endocervical discharge or easily induced endocervical bleeding. Cervical ectopy, if present, may appear edematous. However, at least half of women with gonococcal infection of the cervix have neither signs of MPC nor gonococci detected on Gram stain of endocervical secretions. If symptoms develop, they are nonspecific and typical of most lower genital tract infections: abnormal, increased, or malodorous vaginal discharge; bleeding between menses; menorrhagia; pelvic pain; or pain with intercourse. If cervical infection is left untreated, N. gonorrhoeae may ascend to infect the upper genital tract—including the endometrium, fallopian tubes, ovaries, or adnexa (PID)—or the perihepatic space (Fitz-Hugh-Curtis syndrome). PID is estimated to occur in 10% to 20% of infected women. Finally, abscesses of Bartholin glands are not uncommon.47

Infection at Other Mucosal Sites

Both men and women can be infected at common mucosal sites, including the rectum, pharynx, and conjunctiva. Approximately 35% to 50% of women with endocervical infection are also infected at the rectum, usually without local symptoms. Receptive anal sex is not a prerequisite for rectal infection in women; rather, these infections may result from perianal inoculation with infected cervicovaginal secretions. Men who practice receptive anal sex with other men are also at risk of rectal infection. The presentation of rectal gonococcal infection ranges from asymptomatic colonization detected at routine screening to overt proctitis. Even in symptomatic patients, the range of manifestations is wide, including mild perianal pruritus, painless mucopurulent rectal discharge, mild rectal bleeding, severe rectal pain, tenesmus, and constipation.

Gonococcal infection of the pharynx is rarely symptomatic. Acquired by receptive oral sex (by either fellatio or cunnilingus but more efficiently by fellatio), pharyngeal infection is usually detected through routine screening. In persons with gonococci detected at nonpharyngeal sites, the prevalence of pharyngeal infection ranges from 3% to 7% in heterosexual men, 10% to 20% in heterosexual women, and 10% to 25% in men who have sex with other men.21

Gonococcal conjunctivitis occurs uncommonly in adults. It usually results from autoinoculation, particularly in laboratory and medical personnel.

Disseminated Gonococcal Infection

The term disseminated gonococcal infection refers to gonococcal infections that have spread beyond the genitourinary tract. The most common presentation is the acute arthritis-dermatitis syndrome, which is estimated to occur in 0.5% to 3.0% of persons with untreated mucosal gonococcal infection.48,49 This syndrome may comprise the triad of tenosynovitis, dermatitis, and polyarthralgias without purulent arthritis, or it may appear as purulent arthritis alone. DGI should be strongly considered in any young, sexually active person with acute, nontraumatic oligoarthritis or tenosynovitis.

The arthritis of DGI can affect joints of any size and is typically asymmetrical.50 With tenosynovitis, major tendon sheaths and their insertions are often tender and inflamed; the clinician should palpate these sites if this diagnosis is at all entertained. The classic rash of DGI usually consists of relatively few (< 20) tender, necrotic pustules on an erythematous base that often resolve within several days if left untreated.

Diagnosis of DGI is made more often in women than in men. Predisposing factors include recent menstruation, recent pregnancy, and terminal complement deficiency. The gonococcal strains that cause DGI are often those associated with asymptomatic genital disease and with resistance to complement-mediated bactericidal activity of normal human serum. The organism is recovered by culture from normally sterile sites, including blood or joint fluid, in less than 50% of persons with DGI; however, it can be cultured from mucosal sites or from sexual partners in more than 80% of cases. Amplified nucleic acid assays, such as PCR, have increased the yield of N. gonorrhoeae detection in joint fluid, but a subset of those affected still have sterile joint fluid in the presence of urogenital gonococci, suggesting that immunomodulatory responses are important in the pathogenesis of DGI.51,52

More invasive infection with N. gonorrhoeae is uncommon. Endocarditis and meningitis have been reported, however.53,54

DIAGNOSIS

  1. gonorrhoeaemay be diagnosed presumptively by direct visualization on a Gram stain smear of secretions from a compatible clinical site and, specifically, by growth in culture or detection by antigen detection, nonamplified DNA probe, and a nucleic acid amplification test (NAAT). In men with urethral discharge from N. gonorrhoeae, the organism is seen on Gram stain in 95% [see Figure 1]. Although reasonably specific for detection of endocervical N. gonorrhoeae(> 95%), Gram stain is considerably less sensitive (50% to 70%) and thus not recommended as the sole means of diagnosis of endocervical infection. Gram stain of anoscopically obtained rectal secretions has a sensitivity of 70% to 80% and thus may assist in making a specific diagnosis of gonococcal proctitis.21 Because nongonococcal Neisseriaspecies colonize the pharynx, Gram stain of the pharynx is not specific to infection with N. gonorrhoeae and thus is not recommended.

Traditional bacterial culture remains the mainstay of microbiologic diagnosis for normally sterile specimens in which invasive disease is suspected, such as blood and joint fluid, and is commonly used for the diagnosis of cervical, urethral, pharyngeal, and rectal infections. Cultures are obtained from these sites with a sterile Dacron swab that is then swept across the surface of a plate containing chocolate agar supplemented with glucose, vancomycin, colistin, and nystatin (Thayer-Martin media) and held in an environment with a high level of CO2. The organism grows best under aerobic conditions at 35° to 37° C; however, it can also grow under anaerobic conditions. Unlike N. meningitidis, it does not ferment lactose. Relative to an expanded diagnostic standard that incorporates results of NAAT, culture for N. gonorrhoeae has an estimated sensitivity of 90% and specificity of greater than 99%.55

Other tests commonly used to diagnose gonococcal infection are a nonamplified DNA probe and several types of NAAT. The DNA probe is a nucleic acid hybridization test with a sensitivity of approximately 85% and specificity of 98%.56 Available NAATs include PCR, ligase chain reaction (LCR), transcription-mediated assay (TMA), and hybrid capture tests. In general, the performance of these tests exceeds that of the nonamplification techniques, enhancing sensitivity while maintaining excellent specificity.56 Further, NAATs have the major advantage of performing well on noninvasive specimens: urine in men and, in women, urine and vaginal swabs. Vaginal swabs may be collected either by patients or by clinicians, which provides opportunities for novel screening strategies. The NAATs in general have sensitivities for detection ofN. gonorrhoeae of 95% to 99%, with a specificity greater than 99% for cervical and urethral specimens. However, none is currently recommended for use on specimens other than urine, cervical, or urethral samples.56

TREATMENT

Recommended treatment of gonorrhea varies according to the site of infection and the likelihood of antibiotic resistance [see Table 2]. Currently recommended regimens for the treatment of gonorrhea are available online at http://www.cdc.gov/std/treatment.43

Table 2 Treatment of Gonorrhea1

Disease

Drug

Dosage

Relative Efficacy

Comments

Uncomplicated infection of the cervix, urethra, or rectum*

Cefixime

400 mg p.o. once

First choice

Quinolones not recommended in areas where resistance is a concern; spectinomycin is used for patients intolerant of cephalosporins and quinolones, it is unreliable against pharyngeal infection, and posttreatment cultures are recommended

Ciprofloxacin

500 mg p.o. once

Alternative first choice

Ofloxacin

400 mg p.o. once

Alternative first choice

Levofloxacin

250 mg p.o. once

Alternative first choice

Ceftriaxone

125 mg I.M. once

Second choice

Spectinomycin

2 g I.M. once

Second choice

Conjunctivitis (not ophthalmia neonatorum)

Ceftriaxone

1 g I.M. once

—

—

Disseminated gonococcal infection (DGI)

Parenteral

 

 

Parenteral therapy is given for 24-48 hr after improvement, then followed by oral therapy for 1 wk total antibiotic therapy

  Ceftriaxone

1 g I.M. or I.V. q. 24 hr

First choice

  Cefotaxime

1 g I.V. q. 8 hr

Alternative

  Ceftizoxime

1 g I.V. q. 8 hr

Alternative

  Ciprofloxacin

400 mg I.V. q. 12 hr

Alternative

  Ofloxacin

400 mg I.V. q. 12 hr

Alternative

  Levofloxacin

250 mg I.V. q.d.

Alternative

  Spectinomycin

2 g I.M. q. 12 hr

Alternative

Oral

 

 

  Cefixime

400 mg p.o., b.i.d.

 

  Ciprofloxacin

500 mg p.o., b.i.d.

 

  Ofloxacin

400 mg p.o., b.i.d.

 

  Levofloxacin

500 mg p.o., q.d.

 

Meningitis

Ceftriaxone

1–2 g I.V. q. 12 hr for 10–14 days

—

—

Endocarditis

Ceftriaxone

1–2 g I.V. q. 12 hr for ≥ 4 wk

—

—

Ophthalmia neonatorum

Ceftriaxone

25–50 mg/kg I.V. or I.M. in a single dose, not to exceed 125 mg

—

Topical antibiotic therapy alone is inadequate

*Treatment of gonorrhea in the adult should always be accompanied by treatment of chlamydial infection (azithromycin, 1 g orally in a single dose, or doxycycline, 100 mg orally b.i.d. for 7 days), and patients should abstain from sex during treatment. Test of cure is not routinely recommeded.

The gonococcus has multiple means of acquiring resistance to antibiotics. Plasmid-mediated mechanisms confer resistance to penicillin by encoding altered penicillin-binding proteins (PBPs). Resistance to tetracyclines is mediated by chromosomal mechanisms. Resistance to fluoroquinolones is conferred by production of an altered DNA gyrase to which these antibiotics are unable to bind and hence are rendered ineffectual. The Gonococcal Isolate Surveillance Project (GISP) annually updates important trends in gonococcal resistance patterns (http://www.cdc.gov/ncidod/dastlr/gcdir). Because these patterns can emerge and progress surprisingly rapidly, physicians should be aware of them. Although some problems begin in relative geographic isolation, they often mark the start of significant nationwide trends.57,58,59For example, recommendations for the empirical use of single-dose fluoroquinolone therapy were prominent in the CDC's 1998 Sexually Transmitted Disease Treatment Guidelines; the 2002 document emphasizes that because up to 14% of gonococcal isolates in Hawaii exhibit resistance to fluoroquinolones, these drugs should not be used in this area.60,61 Patients in whom physicians should consider the possibility of quinolone-resistant N. gonorrhoeae (QRNG) include those who (1) have had failures with fluoroquinolone therapy, (2) have traveled to Hawaii or Southeast Asia (where resistance is endemic) or have sexual partners who may have acquired a gonococcal infection there, and (3) reside in California, where recent data indicate an increasing prevalence of QRNG. Because active surveillance is critical, physicians who encounter documented or suspected cases of QRNG should report this to their local health department. In 2000, 25% of GISP isolates were resistant to penicillin, tetracycline, or both. To date, no isolates resistant to cephalosporins have been detected in GISP. Because persons with gonococcal infection are at risk for other STDs, particularly chlamydial infection, the CDC recommends that treatment regimens for gonorrhea be partnered with an antibiotic effective against C. trachomatis as well. Although azithromycin is active against the gonococcus, a dose of 2 g orally is required to effect acceptable cure rates. This is double the dose required to treat chlamydial infection, and such a high dose frequently causes gastrointestinal side effects. Similarly, ciprofloxacin remains effective for gonococcal infections not caused by QRNG, but it is not effective against chlamydial infection. Both infections can be treated with a 1-week course of levofloxacin or ofloxacin, however.

COMPLICATIONS AND PROGNOSIS

The best-known complications of N. gonorrhoeae infection include PID and neonatal conjunctivitis (ophthalmia neonatorum). PID in which gonococci play an etiologic role may be more purulent and severe than PID caused by C. trachomatis. If left untreated, 10% to 40% of women with gonococcal cervical infection will develop PID.62 Ophthalmia neonatorum caused by N. gonorrhoeae can be severe, resulting in perforation of the globe and blindness. Moreover, accruing evidence suggests that gonococcal infection may profoundly impact global morbidity through its role in facilitating transmission and acquisition of HIV. In men infected with HIV, the presence of gonococcal urethritis was shown to increase the quantity of HIV shed in semen by approximately eightfold.63,64 Remarkably, treatment with routine antibiotics aimed at N. gonorrhoeae resulted in significant reduction of the associated HIV shedding.64 Similarly, cervical inflammation in women, commonly caused by gonococcal infection, is associated with increased shedding of HIV; treatment of cervicitis reduces this shedding.65,66These observations suggest that the inflammation associated with gonococcal infection significantly increases the likelihood that HIV may be more efficiently transmitted through unprotected sex. In persons who are not infected with HIV, the same inflammatory cells elicited by gonococcal infection provide a ready target for HIV infection; thus, risk of HIV acquisition is very likely increased in this setting.67

MANAGEMENT OF SEXUAL PARTNERS AND CHEMOPROPHYLAXIS

Persons infected with N. gonorrhoeae should be interviewed and counseled about the importance of treatment for their sexual partners. The CDC recommends that sexual partners with whom patients have had sex within the past 60 days be tested and treated for both gonococcal infection and chlamydial infection.43 If the patient's last sexual contact was more than 60 days before being interviewed, the last partner should be evaluated and treated. For infants, most states require by law that, at birth, an agent be administered to prevent gonococcal ophthalmia neonatorum. Options include single applications of one of several agents, including silver nitrate 1% aqueous solution, erythromycin 0.5% ophthalmic ointment, and tetracycline 1% ophthalmic ointment.

Other Neisseria Species

Several typically nonpathogenic Neisseria species are found as saprophytes in the upper respiratory tract: the nonchromogens N. lactamica,N. mucosa, and N. sicca and the chromogens N. flavescens and N. subflava. All of these species can occasionally cause disease.68,69Meningitis that is clinically indistinguishable from that caused by N. meningitidis has been attributed to each of these species, most frequently to N. subflava and N. mucosa. Endocarditis has also been attributed to nonpathogenic species, particularly N. sicca, N. mucosa, and N. subflava. Odontogenic infections or bite wounds may also harbor these species.70 Infections with nonpathogenic Neisseria species can be treated effectively with penicillin, but occasionally, strains are resistant. The antimicrobial susceptibility of the strain causing the infection should be used to guide therapy.

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Editors: Dale, David C.; Federman, Daniel D.


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