David A. Relman MD
Neisseria gonorrhoeae was first described by Albert Neisser in 1879, in the ocular discharge and exudate from newborn infants with conjunctivitis. Descriptions of a condition resembling the disease gonorrhea can be found in the written record as early as 130 AD, when Galen created a descriptor for the malady by using the Greek words gonos (seed) and rhoea (flow) to characterize what was believed to be the morbid loss of semen. Neisseria meningitidis is thought to be responsible for epidemics in the Napoleonic and Persian armies in the early 1800s. The pathogen was first described in 1886 by Weichselbaum, who observed gram-negative diplococci in the cerebrospinal fluid (CSF) of a young patient who died with purulent meningitis.
Within the family Neisseriaceae, there are five genera—Neisseria, Branhamella, Moraxella, Kingella, and Acinetobacter. N meningitidis and N gonorrhoeae are the organisms that are pathogenic for humans in the Neisseria genus (Table 52-1). Approximately 10 other Neisseria species have been isolated from humans, but these usually establish a commensal relationship with their host and usually do not cause disease. They lack virulence factors, such as pili and virulence-associated outer membrane proteins (OMPs).
Essentials of Diagnosis
The estimated risk of transmission from an infected female to a male by vaginal intercourse is 20% per exposure. The male-to-female transmission risk is less well studied, but is thought to be ~ 50% per contact. Transmission by rectal intercourse is relatively efficient, although it has not been quantified. Infection can also be transmitted perinatally. High rates of promiscuity are required to maintain a high prevalence of gonorrhea in a population. The so-called “core transmitters” of disease are those who frequently have unprotected intercourse with new partners.
although they are usually nonmotile. When grown on solid media, gonococci and meningococci form transparent or opaque, mucoid, nonpigmented, nonhemolytic colonies that are 1–5 mm in diameter.
Table 52-1. Features of Neisseria gonorrhoeae and Neisseria meningitidis
Both N gonorrheae and N meningitidis require specially treated media such as chocolate agar to improve their growth. Chocolate agar is a heme-based growth medium enriched with glucose and other defined supplements; Thayer-Martin medium is chocolate agar with vancomycin, nystatin, and colistin, which inhibit other common commensals, as well as Neisseria species other than gonorrhoeae and meningitidis. Modified Thayer-Martin medium is now commonly used and also contains trimethoprim to inhibit Proteus spp. Growth is optimal at 35–37°C and requires a carbon dioxide-enriched atmosphere. Fatty acids are toxic to N gonorrhoeae; hence, untreated cotton from some clinical swabs may prevent subsequent growth. Neisseria species are strictly aerobic, but, when nitrate is provided as an electron acceptor, these species can grow anaerobically. Neisseria colonies form within ~ 24–48 h on the solid media mentioned above. Neisseria species are usually identified by their carbohydrate utilization patterns. The principal distinguishing metabolic difference between N meningitidis and N gonorrhoeae is that the latter utilizes maltose. Both can generate acid from glucose. The Neisseria species are classified within the beta subdivision of the division Proteobacteria.
Iron acquisition by N gonorrhoeae at the mucosal surface is a critical requirement for survival and growth. This organism and N meningitidis express receptors on their surface for human lactoferrin and transferrin, to capture iron from the host.
Genital infection with N gonorrhoeae most often presents as urethritis in men and cervicitis in women.
The microbiological differential diagnosis for urethritis includes other infectious agents such as Chlamydia trachomatis and Ureaplasma urealyticum.Reiter's syndrome should be considered in patients with urethritis, conjunctivitis, and arthritis. Dysuria and an itching sensation characterize chlamydial urethritis and, in contrast to gonococcal urethritis, may not have profuse purulent discharge. Of men with chlamydial urethral infection, ~ 25% are asymptomatic.
Gonococcal infection in women may progress to involve the uterus and fallopian tubes, causing either acute or chronic salpingitis or pelvic inflammatory disease (PID). Bilateral lower abdominal pain is the most common symptom of PID. There are also signs and symptoms of accompanying lower genital tract infection, as well as cervical-motion tenderness. Fever, leukocytosis, and elevated erythrocyte sedimentation rate or C-reactive protein are common. In PID, anaerobes and chlamydiae may accompany the gonococcal infection. Tubal scarring and infertility are the dreaded sequelae. Perihepatitis (Fitz-Hugh-Curtis syndrome) is a rare complication that occurs by extension of the infection from the fallopian tubes to the peritoneum and the liver capsule. It is accompanied by right upper quadrant tenderness. Laparoscopy demonstrates adhesions between the liver and the parietal peritoneum.
The consequences of gonorrhea during pregnancy include an increased risk of spontaneous abortion, inappropriate rupture of membranes, preterm labor, and fetal mortality. The clinical presentation is essentially the same as that described with genital infection, except that, after the first trimester, PID is less commonly observed because the conceptus obstructs the opening of the uterine cavity. It is unclear whether pregnancy alters the risk for disseminated gonococcal infection.
The cornerstone of diagnosis is the Gram stain or culture. One is looking for gram-negative diplococci associated with neutrophils. Gram stain of urethral exudate from men has a sensitivity of 90% and specificity of 98% when compared with culture. Staining of endocervical exudates is 50% sensitive and 95% specific in the hands of an experienced microscopist. Stained smears of the throat or rectum are not helpful because there are confounding flora that make specific diagnosis a challenge. Cultures need not be done for men in the setting of a positive Gram stain, but are indicated for samples from women or in any case in which there is a question of drug resistance. To cultivate the organism, a swab specimen is streaked on enriched selective medium, such as modified Thayer-Martin, and incubated in 5% carbon dioxide at 37°C. If immediate inoculation with optimal growth conditions is not possible, a transport culture system (ie, JEMBEC) can be used.
In systemic disease, blood culture is necessary. An isolator tube system is preferred. N gonorrhoeae can be cultured from the blood in ~ 30% of cases of gonococcal arthritis. Skin pustule cultures are also useful in defining systemic disease, especially if antibiotic therapy has already been started, because blood cultures will be of lower yield.
Other diagnostic modalities may be used when laboratory culture is not practical or there are specimen transport problems. Assays based on the polymerase chain reaction or ligase chain reaction offer a rapid diagnosis and may offer better specificity and sensitivity than culture; they are becoming more widely available in the United States. Serologic detection of antibodies to gonococcal pili and OMPs by using immunoblotting, radioimmunoassay, or enzyme-linked immunosorbent assay are available for epidemiologic or research purposes but are not clinically useful because of antigenic heterogeneity, the delay in the development of antibody in the setting of acute infection, and the cost.
Many antibiotics are safe and effective for the treatment of N gonorrhoeae (Box 52-1). In choosing a regimen, consideration must be given to the site of infection, other concurrent infections, and the possibility of resistance. The treatment of sex partners is also a crucial consideration in treating any patient with N gonorrhoeae (see Prevention & Control section below). Ceftriaxone in a single dose is the treatment of choice for uncomplicated gonorrhea at all sites. Ciprofloxacin has the advantages of a single oral dose, less expense than ceftriaxone, and effectiveness in patients who are intolerant of cephalosporins; however, resistance has been observed with ciprofloxacin, and it is not active against Treponema pallidum..
Complicated infections or disseminated gonococcal infections, such as arthritis, perihepatitis, or bacteremia resulting in petecchial or pustular skin lesions, require a higher dose of antibiotics than uncomplicated gonorrhea infections and a longer duration of therapy. These regimens should be continued for 24–48 h after clinical improvement is noted (ie, they become afebrile, or joint erythema or skin lesions improve) and then switched to an oral regimen for a total of 7 d. Patients with gonococcal meningitis or endocarditis require higher doses and longer duration of therapy. Meningitis is treated with ceftriaxone for 14 d. Endocarditis should be treated for ≥ 4 wk.
Concurrent infection with C trachomatis is estimated to occur in 40% of those infected with N gonorrhoeae. Therefore doxycycline or azithromycin must be added to the antigonococcal regimen. In pregnant women, for whom doxycycline is contraindicated, an erythromycin base can be used. If erythromycin cannot be tolerated, amoxicillin for 7–10 d is indicated.
Antibiotic resistance has been a major concern, as penicillin resistance has spread and, more recently, fluoroquinolone resistance has been increasingly reported. Beta-lactams remain the drugs of choice in most instances. Antibiotic resistance occurs by one or more mechanisms, including chromosomal mutations leading to decreased penicillin-binding-protein affinity, decreased outer membrane permeability, or beta-lactamase production.
Prevention & Control
The primary measures for prevention of gonorrhea include sexual abstinence and barrier methods with sexual intercourse (“safer sex”) (Box 52-2). Once a case of gonorrhea is identified, treatment of sex partners is an essential element of control of the disease. Epidemiologic treatment refers to the treatment of contacts of patients after a history of exposure to the disease, but without confirmation of infection. This is done in situations in which the risk of unnecessary treatment is outweighed by the risk of developing complications of the infection or the probability of transmission to other contacts. The prevention of gonorrhea must also be considered in sexual assault cases, and antigonococcal medications are included in the recommendations for treatment.
Essentials of Diagnosis
Meningococcal disease usually occurs as isolated cases, but sporadic small epidemics occasionally take place. Group A strains in particular tend to cause widespread epidemics in 8- to 12-y cycles, especially in sub-Saharan Africa (Figure 52-1). The case rates in endemic areas of Africa vary widely, but overall the rate is 10–25 cases per 100,000 population per year. In the United States, the average annual incidence is 1–2 cases per 100,000 population per year. Most cases are seen in children and young adults (ages 5–19 y).
Microbiologic characterization of N meningitidis has been useful in understanding the epidemiology of this disease. The N meningitidis polysaccharide capsule provides the basis for a serogroup typing system. The most important serogroups causing invasive disease are A, B, C, W-135, and Y. These different polysaccharide capsular types are associated with characteristic epidemiological patterns. Group A strains are linked to worldwide epidemics, whereas B and C strains are considered endemic, causing sporadic cases and limited outbreaks. Currently ~ 50% of all cases in the United States are caused by serogroup B and another 20% by serogroup C. The remainder are primarily serogroups Y and W-135. The proportions of disease caused by serogroups C and Y have been rising in recent years. Each serogroup has been further subdivided into serotypes. For example, N meningitidis group B has 12 serotypes based on unique OMPs. These further subtypings of serogroups have been important both for epidemiologic studies and for vaccine development.
Host genetic factors, as well as other cofactors such as passive smoke and concurrent infection in the upper respiratory tract, appear to play a role in the development of meningococcal disease. Viral infection may increase the development of nasopharyngeal infection with N meningitidis, and thus lead to higher carriage rates in households or groups of exposed individuals. It should be noted however that exposure to pathogenic strains of N meningitidis most often leads to a carrier state, but not always to active infection.
The protection provided by the host complement system is demonstrated by the enhanced susceptibility to bacteremic Neisseria disease of those patients who are complement deficient. The importance of another protective factor, specific IgG antibody to N meningitidis, is demonstrated by the increased incidence of serious N meningitidis infection in children between the ages of 6 mo and 2 y. This time interval corresponds to the time between loss of maternal antibodies and the development of natural immunity. Infections in outbreak situations, eg, in young adults, generally represent new infection with a virulent strain in individuals without specific antibodies.
Figure 52-1. Sub-Saharan meningitis belt. Reprinted with permission from Centers for Disease Control. Control and prevention of meningococcal disease and control and prevention of serogroup C meningococcal disease: Evaluation and management of suspected outbreaks: Recommendations of the Advisory Committee on Immunization Practices (ACIP). Morbid Mortal Wkly Rep 1997;46(RR-5):4.
Meningococcal endotoxin, primarily LOS, induces meningococcal sepsis. LOS mediates production of cytokines such as tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1, IL-6, and interferon-gamma. The expression of these host inflammatory mediators results in increased endothelial permeability and myocardial depression and hypotension. Damage to the vascular endothelium results in petecchial or purpuric skin lesions. These lesions reflect a similar process that occurs in multiple organs, leading to shock. Other inflammatory mediators such as prostaglandins, leukotrienes, and platelet-activating factor enhance granulocytic function and intravascular clotting and thrombosis. This in turn leads to disseminated intravascular coagulation, adrenal hemorrhage, decreased vascular resistance, circulatory collapse, and finally death.
BOX 52-1 Therapy for Neisseria gonorrhoeae Infection
BOX 52-2 Prevention and Control of Neisseria gonorrhoeae Infection
N meningitidis causes acute bacterial meningitis with or without meningococcemia. Its potential to progress rapidly mandates early recognition and use of empiric antimicrobial treatment. Pharyngitis precedes meningitis in most patients and is followed by fever with chills and malaise. The classic symptoms of meningitis are headache, nausea and vomiting, and stiff neck. A prominent feature is a petecchial rash that starts distally on the extremities and progresses to the trunk. It often involves the palms and soles. Skin lesions evolve over hours and may continue to develop for a day or more despite appropriate antibiotic treatment (Figure 52-2). Fulminant meningococcemia (Waterhouse-Friderichsen syndrome) occurs in 5–15% of cases. Fulminant disease is associated with vascular collapse, often presaged by apprehension, restlessness, and mental status changes, all developing within a few hours. Acute meningococcemia can occur in the absence of meningitis and presents as the sepsis syndrome.
Figure 52-2. Purpuric rash showing subcutaneous ecchymosis and involving the plantar surface of a patient with meningococcemia. (Courtesy of D Scott Smith, Stanford Univ. Hosp., Stanford, CA).
High fever is usually observed; absence of fever is a poor prognostic sign. Pneumonia from N meningitidis is reported in as many as 15–20% of patients with meningococcemia or meningitis and may occur by itself. Case fatality rates vary according to the prevalence of the disease and socioeconomic conditions. The fatality rate in meningococcal meningitis may be as low as 7% in industrialized countries and as high as 70% for meningococcemia in some developing countries.
Chronic meningococcemia is less common than other bacteremic meningococcal syndromes and presents with fever, headache, rash (90%), and joint pains (66%) that occur intermittently or over a period of days or weeks. The skin lesions occur with the febrile episodes. These lesions are maculopapular (47%) or petecchial (12%) or erythematous and nodular with a pustular center (13%). Without diagnosis and treatment, localized infection such as meningitis, endocarditis, or arthritis develops. Chronic meningococcemia is very responsive to antibiotic therapy.
The diagnosis of meningococcal infection is made by isolation of the organism or detection of its antigen from blood or cerebrospinal fluid (CSF). If possible, blood, CSF, throat swab, and petecchial lesions should be cultured prior to antibiotic use. Collection of these specimens, however, should never delay treatment. Leukocytosis is often as high as 20,000–30,000 cells/mm3. Blood cultures are positive in 50% of cases of meningitis before antibiotics and in ~ 5% of cases after antibiotics are given. Gram stains of skin lesions are positive in ~ 70% of cases. This is a useful diagnostic test especially if antibiotics have been given before the culture specimens could be obtained.
The CSF pleocytosis of meningococcal meningitis is typical of most acute bacterial meningitides with a predominance of PMNs. The CSF glucose is low with a normal or high CSF protein. Gram stain of the CSF is positive in ~ 75% of cases. CSF should be inoculated onto chocolate agar as soon as possible (within minutes) because of the fastidious nature of this organism, like N gonorrhoeae. A latex agglutination test is available and may be indicated for diagnosis in patients treated with antibiotics. This test is expensive and may not improve diagnostic specificity compared with a Gram stain performed by an experienced microscopist. Positive throat and nasopharyngeal cultures in the setting of meningitis should be interpreted with caution, because there are many coincidental meningococcal carriers.
The differential diagnosis is broad, given the clinical presentation of infections caused by N meningitidis. The primary considerations in the setting of meningitis with a rash should include the rickettsial diseases such as Rocky Mountain spotted fever, epidemic typhus, and Brill-Zinsser disease. Toxic shock syndrome caused by Staphylococcus aureus may mimic meningococcemia, and therefore additional appropriate antimicrobial coverage is required. Other diseases to consider include viral exanthems such as infection with echovirus type 9, typhoid fever, and vasculitis syndromes such as polyarteritis nodosa, Churg-Strauss syndrome, and Henoch-Schonlein purpura.
Treatment should be initiated as soon as the diagnosis is considered (Box 52-3). Intravenous penicillin G or ceftriaxone is the standard of therapy. The duration of therapy is dependent on the clinical response, but 7 d is considered adequate for both meningitis and chronic meningococcemia.
The clinical importance of isolates found to have altered penicillin-binding proteins with intermediate resistance to penicillin (MIC of 0.1–1.0 µg/ml) is unclear, as patients with these strains respond well to penicillin. For patients who do not respond adequately to therapy, the bacterial isolate should be tested for antibiotic resistance, and the therapy changed to ceftriaxone or cefotaxime if the isolate is resistant to penicillin.
N meningitidis has traditionally been exquisitely sensitive to penicillin, but recent reports from Spain, England, South Africa, Argentina, Canada, and the United States indicate an increasing percentage of penicillin-resistant strains. A third-generation cephalosporin such as ceftriaxone should be used if there is resistance in the area or if the microbiologic diagnosis might include Haemophilus influenzae or Streptococcus pneumoniae.
BOX 52-3 Therapy for Neisseria meningitidis Infection
Chloramphenicol is effective for meningococcal infection, although there are reports of resistance in parts of sub-Saharan Africa. Although it is usually considered bacteriostatic, chloramphenicol is bactericidal against the meningococcus and achieves high CSF levels. It remains an excellent alternative in beta-lactam-allergic patients and in situations in which multiple dosing of parenteral drug is not feasible. Data to support the use of corticosteroids as adjunctive therapy in meningococcal meningitis are limited.
BOX 52-4 Prevention and Control of Neisseria meningitidis Infection
Prevention & Control
Antimicrobial chemoprophylaxis should be given to close contacts of patients with meningococcal disease, because this is a primary means of prevention of disease (Box 52-4). Close contacts are defined as household members, day care center contacts, and anyone directly exposed to the patient's oral secretions. Antimicrobial prophylaxis should be administered as soon as possible (ideally within 24 h) after case identification, because the secondary attack rate is highest within the first few days of onset of disease in the primary patient. Chemoprophylaxis given > 14 d after the onset of illness in the primary (index) case is of limited or no value. Nasal and oropharyngeal cultures are of no value in determining the need for chemoprophylaxis.
The three antibiotics used for chemoprophylaxis against meningococcal disease are rifampin, ciprofloxacin, and ceftriaxone. Rifampin is the best studied and may be the most efficacious, but it is not the most convenient. It requires multiple dosing, is not recommended in pregnancy, and may cause gastrointestinal side effects. Ciprofloxacin is given as a single dose and is generally well tolerated, but it is not recommended in pregnancy or for children < 18 y of age. Ceftriaxone is also given as a one-time dose but requires intramuscular injection.
A quadrivalent vaccine for meningococcal serogroups A, C, Y, and W-135 is available in the United States. Efficacy varies by age and serogroup. Protection against disease caused by serogroups A and C is 85–100% in older children and adults. The vaccine polysaccharides elicit bactericidal antibody that is serogroup specific. The serogroup B polysaccharide is poorly immunogenic in humans, and thus no useful vaccine against serogroup B is currently available; however, with the recent determination of the complete serogroup B meningococcus genome sequence, a set of immunogenic outer surface proteins from this organism has been revealed. A candidate vaccine has been created from some of these proteins. Serogroup B is the most common cause of meningococcal disease in Europe, North America, and several countries in Latin America.
Vaccine protection decreases over time and more rapidly in young children. In children older than 4 y, one study documented an efficacy of 67% at 3 y after vaccination. The current vaccine is useful in controlling serogroup C meningococcal outbreaks. It is also recommended in the following high-risk groups: (1) complement-deficient hosts (C3, C5–C9), (2) asplenic individuals, (3) travelers to endemic areas, (4) research or laboratory personnel, and (5) military recruits.
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