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 meningo-coccal 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
Immunization
Vaccine
A quadrivalent polysaccharide vaccine for protection against N. meningitidis serogroups A, C, Y, and W-135 (Meno-mune) is currently available.35 It is administered subcutaneous-ly 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 immuno-protection 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 asple-nia. 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 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:XX1I 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 auxotyp-ing, 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 transfer-rin 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 neu-trophils 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.
Clinical presentations
N. gonorrhoeae is 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 seropu-rulent, 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.21 The 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 endocer-vical canal, where N. gonorrhoeae may cause mucopurulent cervicitis (MPC). MPC presents as either mucopurulent endocer-vical 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 en-dometrium, 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 gono-coccal 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. gonor-rhoeae 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.
More invasive infection with N. gonorrhoeae is uncommon. Endocarditis and meningitis have been reported, however.
Diagnosis
N. gonorrhoeae may 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 nongono-coccal Neisseria species 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 micro-biologic 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, pharyn-geal, 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 non-amplification 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 of N. 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 www.cdc.gov/std/treatment.43
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.57-59 For 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, tetracy-cline, 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. trachoma-tis as well. Although azithromycin is active against the gono-coccus, 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 neonato-rum). 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 gono-coccal 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.65,66 These 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.
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 cephalospo-rins 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 recommended.
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 infec-tion.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 nonchro-mogens N. lactamica, N. mucosa, and N. sicca and the chro-mogens N. flavescens and N. subflava. All of these species can occasionally cause disease.68,69 Meningitis that is clinically indistinguishable from that caused by N. meningitidis has been attributed to each of these species, most frequently to N. subfla-va and N. mucosa. Endocarditis has also been attributed to non-pathogenic species, particularly N. sicca, N. mucosa, and N. sub-flava. 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.
