Gonococcal Infections

Epidemiology and Transmission

The incidence of neonatal gonococcal illness is related to the prevalence of N. gonorrhoeae colonization among women of childbearing age and to the rates of gonococcal acquisition during pregnancy. These numbers are quite variable worldwide. In general, when antibiotic treatment for gonorrhea became available in the mid-20th century, rates of infection among women decreased worldwide as these agents became more readily accessible and health care programs improved. However, with the emergence of chromosomal resistance to penicillin, the production of penicillinase by some strains, and the expansion of the AIDS epidemic in the 1990s, rates began to increase again. In response, efforts to control this infection, which some authorities had hoped could ultimately be eliminated by the middle of the 21st century, have needed to be strengthened.

The World Health Organization published estimates of the burden of gonorrheal disease in various regions at the end of the 20th century. Although these estimates are useful in highlighting regions of high burden of disease, such as sub-Saharan Africa and South/Southeast Asia, with an estimated 17 million and 27 million infections, respectively, considerable variation within regions exists. This variation is clearly reflected in the differences seen in the reported cases of gonorrhea the United States in 2011, the most recent year for which this data has been compiled. In the United States during that year, the prevalence was 104.1 per 100,000. Rates varied across the country, with Vermont having the lowest prevalence at 7.7 per 100,000 and the District of Columbia having the highest at 429.9 per 100,000. Overall, the prevalence among women was higher than men (108.9/100,000 vs. 98.7/100,000, respectively). The highest rates were seen among women 15 to 19 years of age (556.5/100,000) and 20-to 24-year-olds (584.2/100,000). Further significant differences are noted among specific populations. The United States has set a goal of reducing the national prevalence of gonorrhea to less than 19 cases per 100,000 among adults; however, that goal is unlikely to be met in the near future.

Canada has placed an emphasis on STD control also and has an exclusively publicly funded health care system that in theory reduces a number of health care access barriers. Gonorrhea prevalence rates have decreased from 1980, when the prevalence among women was 166/100,000 population. The highest rates at that time were among women 15 to 19 years of age and 20 to 24 years of age, which were similar to the United States prevalence at 510 versus 598 per 100,000, respectively, in 2011. In 2008, the prevalence among women in Canada was approximately 34 per 100,000, which represents a significant increase from 1997, when rates were the lowest at 11 per 100,000. The increase has occurred primarily among women 15 to 19 years of age and 20 to 24 years of age; in these age groups, rates rose from 69 and 60 per 100,000, respectively, in 1997 to 186.6 and 166.3 per 100,000, respectively. Also, as in the United States, rates in Canada vary considerably among the different provinces and territories. In 1997, Canada set as its goal the elimination of endemic transmission of N. gonorrhoeae by 2010. Similar to the United States, Canada has not met its goals. The reasons for the rate increases in Canada and the failure to eliminate endemic transmission are complex, but a proportion of the increase is likely related to the almost universal change in diagnostic procedures in Canada from culture to nucleic acid–based testing, which includes the use of urine specimens. Nucleic acid–based testing is considerably more sensitive than culture, thereby increasing the number of infected individuals identified and is more acceptable to patients, thereby increasing the number of infected individuals who present for testing.

Factors that increase a pregnant woman’s risk of acquiring N. gonorrhoeae infection are similar to the factors that increase the risk of acquisition of any other sexually transmitted infection. The prevalence of N. gonorrhoeae in the population or network in which a woman socializes and chooses her sexual partners determines the likelihood of exposure to this pathogen. Women who have multiple sexual partners or whose partners have multiple sexual contacts markedly increase their risk of exposure to N. gonorrhoeae . Women who do not use condoms or other barrier protection increase their risk of acquisition of N. gonorrhoeae infection on exposure to the organism. Women and their partners who do not have convenient access to medical care or who do not seek available care for diagnosis and treatment of STIs will have higher rates of infection. It is unknown whether women who are HIV positive have an increased risk of infection by N. gonorrhoeae on exposure to it. Factors that are markers for an increased likelihood of gonococcal infection among pregnant women include younger age, unmarried status, homelessness, problems with drug or alcohol abuse, prostitution, low-income professions, and, in the United States, being black. Gonococcal infections are diagnosed more frequently in the summer months in the United States, probably reflecting transient changes in social behavior during vacations.

N. gonorrhoeae is primarily transmitted from the infected maternal cervix during vaginal delivery. It has been estimated that colonization and infection of the neonate occur in only one third of instances in which the mother is infected. The infant’s mucous membranes become colonized on swallowing contaminated fluid during labor and delivery. In instances of an ascending infection, the consequences include premature rupture of the membranes with early onset of labor with premature delivery or septic abortion. This association was dramatically shown in one study in which premature rupture of membranes occurred in 6 (43%) of 14 women with untreated gonococcal infection during pregnancy, compared with 4 (3%) of 144 women whose infection had been appropriately treated. Thus screening and treatment programs for gonococcal infections during pregnancy are appropriate to reduce the risk of adverse pregnancy outcomes related to maternal infection in addition to prevention of ophthalmia neonatorum.

Worldwide, there has been concern about the development and transmission of antibacterial resistance among isolates of N. gonorrhoeae . Newer testing protocols that involve nonculture techniques have made tracking the development of antibiotic resistance more difficult. Fortunately, in the United States, antibiotic resistance among gonococci has been monitored systematically since 1986 by using selected STD clinics through the Gonococcal Isolate Surveillance Project. In 2011, 31.1% of gonococcal isolates in the United States were resistant to at least one antimicrobial agent; 11.8% were resistant to penicillin and 16.9% were resistant to tetracycline. Once the resistance rate to an antibiotic is 5% or more, the involved drug is not recommended for general use to treat gonococcal infections. As a result, in the United States penicillin is no longer recommended for primary therapy for gonococcal disease, and tetracycline ointment is not recommended for newborn ocular prophylaxis.

Microbiology

N. gonorrhoeae is a gram-negative diplococcus. It uses glucose for growth but not maltose, sucrose, or lactose. This is one of the characteristics used to distinguish N. gonorrhoeae isolates from Neisseria meningitidis and other colonizing Neisseria species, such as N. cinerea, N. flava, N. subflava, N. lactamica, N. mucosa , and N. sicca . N. gonorrhoeae produces acid only when grown in glucose. In addition, the organism is oxidase positive, hydroxyprolyl aminopeptidase positive, nitrate negative, DNase negative, catalase positive, strongly superoxol positive, and colistin resistant. N. gonorrhoeae is an obligate aerobe but lacks superoxide dismutase, which moderates the effects of oxygen radicals in most other aerobic bacteria. When grown in anaerobic conditions, virulent strains express a lipoprotein called Pan 1. Its function is unknown, but it elicits an immunoglobulin M (IgM) antibody response in acute infection.

When cultured in the laboratory, N. gonorrhoeae forms three different colony types. Pinpoint colonies, classified as P ⁺ and P ⁺⁺ , usually are seen only on primary isolation. These colony types are distinguished from the large granular colonies, classified as P ⁻ , by the presence of pili, which are thin bacterial appendages on the cell surface that are involved in attachment to mammalian cells and which confer resistance to killing of the bacteria by neutrophils. N. gonorrhoeae has the genetic capacity to turn on and turn off pilus expression. With repeated subculturing at 37° C, the genes are no longer expressed, and the pili disappear, resulting in colonial-type changes. Associated with this change is a reduction in virulence. N. gonorrhoeae also may form colonies that are either opaque or clear. This characteristic is related to the expression of a specific surface protein called Opa. Clinical isolates from mucosal surfaces tend to express Opa and form opaque colonies, whereas gonococci isolated from systemic infections tend not to express Opa, and the colonies are more transparent on culture media.

Colonial morphology is of no use in differentiating gonococcal types or strains. Typing of gonococcal isolates for epidemiologic purposes has changed significantly over the past decade with the introduction of newer technologies. The older typing schemes using a combination of auxotyping (use of growth requirements) and serotyping of porins (proteins on the cell membrane that provide channels to allow substances into the bacterial cell) has been replaced with hybridization patterns of porB or DNA sequencing of porB (one of the genes that code for porins). Use of pulse-field gel electrophoresis of bacterial DNA and multilocus sequence typing are very helpful for epidemiologic studies.

Pathogenesis

To produce infection, N. gonorrhoeae first attaches to epithelial cells, penetrates, and then destroys the infected cells. Attachment to epithelial cells is related to the presence of pili and Opa. Penetration of the gonococcus into cells occurs through either phagocytosis or endocytosis. Several bacteria usually are found within each infected cell, but whether this represents invasion of the cell by multiple organisms or growth and multiplication of organisms within the infected cell is unknown. Gonococci possess a cytotoxic lipopolysaccharide and produce proteases, phospholipases, and elastases that ultimately destroy the infected cells. Some strains of gonococci seem to be relatively less susceptible to phagocytosis and are thought to be more capable of causing disseminated infection. Gonococci are found in the subepithelial connective tissue very quickly after infection. This dissemination may be due to the disruption of the integrity of the epidermal surface with cell death, or the gonococci may migrate into this area by moving between cells. Epithelial cell death triggers a vigorous inflammatory response with the development of small abscesses below the mucosal surface and the production of pus. Initially, this is primarily due to neutrophils but is then replaced over time by macrophages and lymphocytes if the individual is not treated.

Human serum contains IgM antibody directed against lipopolysaccharide antigens on the gonococcus, which inhibits invasion. An IgG antibody directed against a surface protein antigen present on some gonococci (classified as serum-resistant gonococci) will block the bactericidal action of the antilipopolysaccharide IgM antibody. These serum-resistant strains are the most common ones involved in systemic infections in adults and probably in neonates as well. Infants’ sera, in which maternal IgM antibody is absent, do not show serum bactericidal activity against N. gonorrhoeae ; in theory, infants should be highly susceptible to invasive infection. Because such infection does not occur frequently, additional protective factors must function to prevent it.

N. gonorrhoeae produces an IgA1 protease, which inactivates secretory IgA by cleaving it at the hinge region. This inactivation facilitates mucosal colonization and probably plays a role in the poor mucosal protection seen against subsequent gonococcal reinfection. IgA1 protease is also a proinflammatory factor and can trigger the release of proinflammatory cytokines from human monocytic subpopulations and a dose-dependent T-helper type 1 T-cell response. Although symptomatic gonococcal infection stimulates a brisk inflammatory response, it does not produce a significant immunologic response. There is very little immunologic memory; as a result, recurrent infections occur easily on reexposure. In general, antibody responses are modest after initial infection, however, and no evidence of a boosting effect has been found when antibody levels are studied in response to subsequent infections.

Adults with mucosal gonococcal infections have a discernible decreased CD4 ⁺ count, which recovers with treatment or clearance of the infection and has led to speculation that gonococci actually have a suppressive effect on the host immune response. In support of this theory, N. gonorrhoeae Opa proteins have shown to be able to bind carcinoembryonic antigen–related cell adhesion molecule 1, expressed by primary CD4 ⁺ T lymphocytes, and to suppress their activation and proliferation. This immunosuppressive effect may have significant consequences in populations with coexisting epidemics of gonorrhea and HIV/AIDS.

Because only approximately one third of neonates exposed to N. gonorrhoeae during vaginal delivery become colonized and infected, additional protective innate factors are in effect. Significant antibacterial polypeptide activity has been shown in human amniotic fluid and within the vernix caseosa. The presence of numerous antibacterial polypeptides in the vernix may be important for surface defense against gonococcal infection, but specific studies have not yet been done.

As stated previously, antibiotic resistance in N. gonorrhoeae to penicillin, tetracycline, quinolones, cephalosporins, macrolides, and spectinomycin has become problematic in many regions. Penicillin resistance can be a result either of alterations in the penicillin-binding proteins or changes in antibiotic efflux (which are encoded on the bacterial chromosome) or the production of a penicillinase. At present, chromosomally-mediated resistance is the predominant mechanism for penicillin resistance in North America. The alterations responsible for chromosomal resistance to penicillin include the mtr gene mutation, which increases efflux of antibiotics out of the bacterial cell and which affects several other antibiotics in addition to penicillin; the penA gene mutation, which alters the penicillin binding proteins; and the penB gene mutation, which affects the antibiotic transit through the bacterial membranes. N. gonorrhoeae can accumulate several mutations, resulting in resistance to multiple classes of antibiotics. Of recent concern has been the effect of these mutations (which may have been transferred to N. gonorrhoeae from nonpathogenic oral Neisseria on a DNA cassette that contained multiple penA mutations) on increasing the minimal inhibitory concentrations (MICs) of third-generation cephalosporins. This has resulted in an increase of the recommended dosage of these antibiotics for treatment of gonococcal infections. Although not applicable to the pediatric population for systemic use, high levels of resistance rapidly developed for both tetracycline and quinolone classes of antibiotics and eliminated their potential for topical use to prevent infection.