Research on Gonorrhea

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Gonorrhea is the second most common sexually transmitted disease in the United States today. It accounts for more than three hundred thousand cases annually. There is concern that due to the low rate of reporting cases of gonorrhea, almost the same number(300,000 cases) goes unreported annually. In men Neisseria gonorrhoeae; the etiologic agent of gonorrheal infections have been incriminated in urethritis while in women cervititis; which can progress to pelvic inflammatory disease(PID), ectopic pregnancy, infertility and pelvic pain. Invasive infections include disseminated gonococcal infections(DGI), meningitidis and endocarditis. The latter two are considerably uncommon but they can result in serious morbidity(Leone et al 2008; Hay et al 2000).

Epidemiologically, overall rates of infections have plummeted since the mid-1970s to a rate of approximately 116.2 cases per 100, 000 cases by the end of 2003(Leone et al 2008). Despite these statistical representations of overall decline in gonorrheal cases, racial disparities still persist and antibiotic resistance has been on the increase. The reasons behind this disparity in reduction is attributable to geographical clustering of the populace, differences in accessing and utilizing health services, sexual partner choices coupled to a set of complex and interrelated socioeconomic influences. Differential reporting by members of the public can also magnify the statistical racial disparity.

Neisseria gonorrhoeae

Neisseria gonorrhoeae is a Gram- negative , non motile, non spore forming diplococcus belonging to the family Neisseraiceae(Gaydos & Quinn 1998). It is the principal etiologic agent of gonorrhea. Other pathologic species in the same family is Neisseria meningitidis. These two species are genetically related but N. meningitidis is not usually taken as an etiologic agent of a sexually transmitted disease. However, it can infect the mucous membranes in the anogenital area among homosexual men(Janda 1983). Both bacteria are classified as pyogenic cocci since their infections are characterized with the production of purulent material composed of white blood cells. The genus Neisseria is also composed of other species; Neisseria lactamica, Neisseria cineria, Neisseria polysaccharea and Neisseria flavescens. These species are comparatively more related to Neisseria gonorrhoeae than the saccharolytic strains like Neisseria sicca, Neisseria subflava and Neisseria mucosa. The latter species are basically non pathogenic normal flora resident in the nasopharyngeal mucous membranes(Knapp 1995).

Structurally, Neisseria gonorrhoeae are unencapsulated, non motile, pilated organisms that have a pair of kidney beans like appearance. These pili are hair like surface appendages made of helical aggregates of subunit peptide repeats referred to as pilin. These structures are used by the organism to attach onto mucosal and epithelial cell surfaces as well as to confer resistance to phargocytic action. The pili acts as an important virulence factor. Pili are also antigenic. The existence of at least twenty gonococcal genes that code for pili confer the bacteria with the ability to synthesize and express multiple pili at different times. Neisseria gonorrhoeae also possess gonococcal lipooligosaccharides (LOS) that have shorter and more branched non repeat O-antigenic side chains. The outer membrane proteins(OMPs) confer antigenic diversity among the different strains of Neisseria gonorrhoeae. OMP I functions as a porin complex with OMP III. OMP II; the opacity protein, renders gonococcal colonies less translucent. Together with pili, OMP II, mediate host cell attachment and it is due to its extensive antigenic variation that the organism is able to significantly evade the immune response and launch repeated infections(Harvey et al 2006).

Clinical Significance of Neisseria gonorrhoeae

Gonorrhea is the second most prevalent sexuality transmitted disease of bacterial etiology (Hay et al 2000). Infections involving Neisseria gonorrhoeae may either present as symptomatic or asymptomatic and cause cervicitis, urethritis, proctitis, conjuctivitis or Bartholinitis. In men, gonorrhoeae infections may cause complications such as prostatitis, epididymis and seminal vesiculitis. With regard to homosexuals, pharyngitis and rectal infection may also occur. Among females, many Neisseria gonorrhoeae infections are asymptomatic and includes complications in the rectum and urethra. In most cases these complications may coexist with cervical infection. Complications may also include pelvic pain, pelvic inflammatory disease, ectopic pregnancy, infertility, premature labor, spontaneous abortion, chorioamnionitis, infections of the neonate as well as Fitz-Hugh Curtis syndrome(Gaydos 1998).

Neisseria gonorrhoeae colonize the genitourinary tract or rectum mucous membranes. After colonization they cause a localized infection that is characterized with the production of pus. In some cases these organisms invade tissues, cause chronic inflammation and fibrosis. Since infections in females are mainly asymptomatic, they act as infection reservoirs for the maintenance and transmission of the disease. It is prudent to note that more than a single sexuality transmitted infection can be acquired or transmitted at any given time.

Infections that are localized in the genitourinary tract are more acute ans much easier to diagnose among males. Symptomatically, the patient presents with a yellow and purulent urethral discharge as well as experiences of pain during urinating. On the other hand, in females where the infection is localized in the endocervix extending to the urethra and the vagina, the most common symptom is a greenish yellow cervical discharge. In most cases intermenstrual bleeding accompanies this cervical discharge. Progression to the uterus causes salpingitis, pelvic inflammatory disease and fibrosis. Statistics show that about 20% of women diagnosed with gonococcal salpingitis may develop infertility as a result of tubal scarring.

As aforementioned, rectal infections are mainly concentrated among homosexuals. Symptomatically, the infection presents as painful defecation, constipation and purulent discharge. Pharyngitis only develops in cases where there is oral-genital discharge. A purulent exudate may be observed and pharyngitis mimics streptococcal sore throat or a mild viral infection. Ophthalmia neonaratum; an infection of the newborn that is caused by the passage of the mothers infection to the newborn during childbirth. This infection of the conjuctivial sac  or rather acute conjuctivitis, if left untreated may result to blindness. Usually treatment with erythromycin serves not only to eradicate Neisseria gonorrhoeae but also Clamydia trachomatis. Gonococcal conjuctivitis is not only limited to the newborn as it can also occur in adults(Harvey et al 2006).

Usually strains of N. gonorrhoeae possess a limited ability to multiply in the hosts’ bloodstream. Thus, cases of bacteremia are extremely rare. This is a distinguishing feature between N. gonorrhoeae and N. meningitidis which rapidly multiply in the hosts bloodstream. For stains that invade the bloodstream and lead to the development of bacteremia, they cause painful purulent arthritis, fever and small scattered pustules on the skin. These pustules have an erythematous bases and may develop necrosis. Dissemination of infection is prevalent in both sexes, but more prevalent in females during menses and pregnancy(Harvey et al 2006).

Identification, Isolation and Classification of  Neisseria gonorrhoeae

Since, N. gonorrhoeae does not multiply and persist in the bloodstream for the quantity and duration necessary for a conclusive identification and isolation, laboratories prefer, urine or urethral exudates as the most reliable samples for analysis. From male urethral exudate samples, the presence of numerous neutrophils with gram positive diplococci in the smear constitutes a provisional diagnosis of gonorrhea. However, to make a positive diagnosis as regards female samples or male samples other than urethral exudates(for instance joint fluid, blood and skin lesions), culturing is necessary.

Prior to the acquisition of specimens for the isolation of N. gonorrhoeae it should be taken into account that the bacteria has the capacity to infect several sites simultaneously. This implies that collection is dependent on the patterns of sexual practices. In cases where gonococci and meningococci have to be transported over long distances hence delay of isolation it would be appropriate to submit an unstained smear this is to eliminate the inhibitory effect. Apart from swab collections, urine centrifugates can be used as they are more recommended for gonococcal culture. Samples are incubated in culture medium at a temperature of 35-37°C, CO₂ supplementation and added humidity. In most cases, a plain candle non toxic jar is adequate or an incubation chamber for larger laboratories. Both the selective and non selective media may be used in the analysis of samples.

However, for gonococci, a non selective media my require enrichment with co-factors, amino acids and additives like Isovitalex or the equivalent. These supplements ensure the growth of fastidious auxotrophs. Selective media usually contain the latter’s solid base infused with colistin, trimethoprin, vancomycin and an antifungal agent. The most common selective medium in use currently is the Martin-Lewis, New York City media and the modified Thayer-Martin medium. Culturing usually takes at most 72 hrs. Since some gonococci such as auxotrophs are susceptible to the antibiotic vancomycin, it is recommended that in the isolation of gonococci the benefit of another selective medium should be exploited(Cimolai 2000).

Based on either oxidase test or colony morphology in selective media, the mere demonstration of growth under all the essentials for growth is enough to raise the concern for N. gonorrhoeae. The production of acid in CTA sugars(glucose, fructose, lactose, sucrose and maltose) confirms identification. Alternatively, immunoflourescence using specific species polyclonal or monoclonal antibodies interpreted through confirmatory agglutination reactions or DNA probes can be used to definitively identify and isolate N. gonorrhoeae(Coghill & Young 1987; Cimolai 2000). DNA probing is the current identification methodology owing to the problems with gonorrhea. This method involve direct genetic detection using commercial investigative DNA probes.

Based on the Interbantional Statistical Classification of Diseases and Health Problems(commonly abbreviated as ICD), disease are classified and allocated codes that are descriptive of a variety of signs, symptoms, complaints, abnormal findings, the social circumstances as well as the external causes of disease or injury. Classified under ICD-10 code, gonorrhea lies at Chapter XIV, Block N00-N99 which is a classification of diseases of the genitourinary system, and gonorrhea has the code A54. (WHO). In the list of ICD-9 it is coded under 580-629: Diseases of the genitourinary system, as 098.

Pathogenesis

Uncomplicated cases of gonorrhea include an acute urogenital infection that involves the urethra in men and endocervix in women who have reached the reproductive age. In some cases infection can also occur on the female urethra, rectum or pharynx. In girls of the prepubescent stage of development and the post menopausal women, infection presents as virginitis as opposed to as cervicitis. This age dependent difference in the nature of infection is a result of differences in the histology of the endocervical region. Upon entrance in the urogenital tract, N. gonorrhoeae facilitate adherence to columnar cells hence withstanding the flushing force of urine in the urethral tract as well as the continual cervical mucus shredding. Adherence to the epithelium is aided by the pili and the functionally associated gonococcal lipooligosaccharides; OMP II and opacity proteins(Jerse 2000).

Human membrane co-factor protein(CD46) acts as the receptor for the N. gonorrhoeae pili. Ironically, it is the same human membrane molecule that serves as measles virus host cell receptor. The opacity proteins(Opa) bind to the host cells’ CD66 glycoproteins which are a subset of the carcinoembryonic family(Apicella et al 1996). Consequently, Opa mediated adherence induces the uptake of the bacterial cells by the neutrophils and the epithelial cells. This mode of entry into the cell have been visualized in tissue culture assays, visualization of N. gonorrhoeae within cervical and urethral cells as well as in the subepithelium of an endometrial tissue that have been excised from a 10 week case in an infected woman(Jerse 2000; Apicella et al 1996). Polarized epithelial cell intracellular invasion studies suggest that invasion of the subepithelium occurs via the traversal through the epithelial cellular lining.

Invasion of the subepithelium promotes the subepithelial space access and hence the entry of the bacteria into the bloodstream hence the disseminated gonococcal infection(DGI). Locally disseminated infection of the locally ascended infection occurs when when N. gonorrhoeae ascends from the lower genital tract to higher tissues or organs in the genital tract like epididymitis in men and endometricitis, pelvic peritonitis and salpingitis in female patients. These manifestations in the female genital tract are collectively referred to as pelvic inflammatory disease(PID). N. gonorrhoeae species selectively adhere to non ciliated secretory fallopian tubes cells. Invasion of the subepithelium occurs via the epithelium and the adjacent cells.  Gonococcal cells secret toxic lipooligosaccharides(LOS) that exfoliate ciliated cells hence reducing ciliary activity. Extensive damage to the female reproductive tract may lead to an irreversible case of infertility. In addition to the primary gonococcal infections, postinfection complications may include ectopic pregnancies, chronic pelvic pain, and a life threatening case originating from the fallopian tubes scarring(Jerse 2000).

There is no conclusive evidence to explain the mechanisms by which the pathogen ascends the female reproductive tract but avenues like traveling while attached to spermatozoa or reflux of menstrual blood form the major hypotheses to this end. Locally disseminated gonococcal infections are more prevalent(for instance between 10-20% of patients with gonococcal cervitis). Systematically disseminated gonococcal infections(DGI) have been observed in 0.5-3.0% of patients presenting untreated cases of mucosal infections(Jerse 2000). Hematogenous spread of the bacterial infection to the skin and joints causes acute dermatitis and arthritis respectively. In DGI, infection presentation as endocarditis is less prevalent. DGI occurs in most women within seven days after menstruation.

N. gonorrhoeae is equipped with mechanisms of persistence that allow it to avoid or in some cases capitalize on the hot factors it encounters during infection. Most importantly, the bacteria has transcriptional regulation mechanisms of genes to provide an effective response to the stimuli in the mucosal layer. This among other persistence mechanisms enable the bacteria to gain entrance into the human body through nutritionally different micro environments as well as counter the physiological stress induced by a variety of non specific host defenses(Jerse 2000).

Treatment and Prevention of Gonorrhea

There are a wide range of antibiotics can be used to treat gonorrheal infections. In choosing the correct regimen for an effective treatment program, crucial consideration is given to the site of infection, the presence of other concurrent infections and the possibility of antibiotic resistance(Wilson et al 2001). They include amoxallin, azithromycin, ampicillin, cefixime, cetotaxime, ceftriaxone, cefpodoxime, levofloxacin, and spectinomycin. These drugs have distinct dosages levels but they are all administered in a single dose. Tetracycline is also a drug of choice in the treatment of gonorrheal infections but the level of resistance exhibited by many strains of N. gonorrhoeae across different parts of the world makes it an ineffective option in the management of diarrhea.

Flouroquinones(levofloxacin, ciprofloxacin, ofloxacin) cannot be administered during pregnancy. However, in the event that a pregnant woman presents herself for treatment, it is crucial that all the partners be encouraged to seek treatment and be screened for the presence of other sexually transmitted diseases. Since co infection with clamydia is extremely common, a combination of antibiotics such as administration of ceftriaxone with azithromycin or doxycycline is effective in treating the two infections of bacterial etiology. During treatment, patients should refrain from engaging in sex to avoid reinfection. Patients who have been diagnosed with rectal gonorrhea should not used penicillin medications since bacterial populations in the rectum produce ß lactamases that destroy penicillin making them ineffective.

In the United States, a third generation cefriaxone is the most recommended antibiotic against gonorrheal infections but due to higher antibiotic resistance in some areas like California and Hawaii the flouroquinones are not recommended fro the empirical treatment of diarrhea.

The primary prevention measures are abstinence and the use of barrier methods such as condoms. In addition to these, behavioral interventions also form the most common strategies employed in the prevention of gonorrhea infections. These strategies basically include delaying the sexual debut and reducing sexual activities with several partners. It is recommended that individuals reduce the behavioral tendency of acquiring new partners while ensuring that condom usage is maintained with the remaining sexual partner. When condoms are used consistently, there is significant reduction in the transmission of gonorrhea. Among females, the polyurethane condom is preferable but it is least effective in preventing gonorrheal transmissions in comparison to the male condom. Apart from this significant ineffectiveness the female polyurethane condom has also faced chronic non compliance  and unacceptability among couples(Wilson et al 2001).

Another prevention measure is to ensure that all individuals diagnosed with gonorrheal infections be treated within three months. All sexual contacts of anybody with a a diagnosis of gonorrhea should be identified and encouraged to seek treatment. Usually, in most cases doctors advise partners seeking treatment to notify their sexual partners to undergo screening and treatment. Other treatment programs allow a partner to present medication to their partners. These treatment programs describe what is popularly referred to as epidemiologic treatment. This treatment program can be simply defined as the treatment of patients based on a history of exposure to infection without necessarily confirming the presence of an infection.

Apart from behavioral interventions, there are a wide array of research on the effectiveness of several rectal and vaginal microbicides or antimicrobial gels that can be used by both partners during sexual intercourse to prevent the transmission of these infections. In cases of sexual assault antigonococcal medications are administered even before the possibility of such an infection is confirmed.