Gonorrhoea (Neisseria gonorrhoeae) in the United States: Difference between revisions

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[[Image:Gram_stain.jpg‎|frame|right|Gram-stain of a urethral exudate that is diagnostic of gonococcal urethritis. Image courtesy of CDC.]]
==Introduction==
==Introduction==
[[Image:Gonorrhea.jpg|thumb|Neisseria gonorrhoeae. Image courtesy of CDC/Dr. Norman Jacobs]]


Globally, gonorrhea is one of the most commonly transmitted venereal diseases. First used in the second century by Aelius Galenus, a Roman physician and philosopher, the term literally translates to “flow of seed” [2]. In the sixth century, the disease and treatments of pelvic abscesses caused by gonorrhea is described by a Byzantine physician and medical writer, Aetius Amidenus. The disease also became prevalent in France, being well known by one of its symptoms as ‘La chaude pisse’ which meant hot piss. [1] In 1879, a German physician and bacteriologist, Albert Ludwig Sigesmund Neisser was the first person to describe the bacterium, Neisseria gonorrhoeae as the causative agent of gonorrhea.
[[Image:Albert_Neisser.jpg|frame|left|Albert Ludwig Sigesmund Neisser, discoverer of the pathogen N. gonorrhoeae.]]


==Neisseria Gonorrhoeae==
With over 600,000 new infections reported each year, ''Neisseria gonorrhoeae'' (''N. gonorrhoeae'') has become the second most common, sexually transmitted infection in the United States. With its incidence only second to ''Chlamydia trachomatisa'' [5], the most disturbing fact of ''N. gonorrhoeae'' lies in the reality that it shows no discrimination among the sexually active - anyone and everyone is susceptible. The group most at-risk are sexually active women under the age of twenty-five and African American men [3]. Other risk factors include previous gonorrheal infection, diagnosis of other sexually transmitted diseases, new or multiple partners, inconsistent-to-no condom use, commercial sex work, as well as drug use [5]. Notable symptoms in males may include swollen and painfully sensitive testes, a white, yellow, or green penal discharge, a burning sensation while urinating, and/or the formation of unusual sores/a rash. In females, symptoms may include a painful or burning sensation while urinating, vaginal bleeding between periods, and/or increasing vaginal discharge. Due to the fact that the majority of those infected are asymptomatic, especially among women, if left untreated, the infection can result in the sterility in either sexes and in extreme cases, lead to their fatality [5]. Thus, the only factor keeping the infection from developing into an epidemic rests upon people routinely getting tested. Fortunately, because ''N. gonorrhoeae'' is a bacterium, curable treatment is available. However, this relief is currently being threatened. 


===Description of the Microbe===
===History of the Name ''Neisseria Gonorrhoeae'' (''N. Gonorrhoeae'')===


Neisseria gonorrhoeae (N. gonorrhoeae) is a gram-negative diplococcus ranging from 0.06 to 1.0 µm in diameter and is usually seen in pairs with adjacent flattened sides. The organism is typically observed inside polymorphonuclear leukocytes (neutrophils) that have become a part of the gonorrhea pustular exudates. Fimbriae are used by the bacteria for adherence, extending several micrometers from the cell surface [2]. N. gonorrhoeae have antigenic type IV pilus and the opacity (Opa) proteins. It moves by long pili that are constituted of repeated peptide subunits (pilin) characterized by both antigenic and phase variations. The bacterium is able to rearrange its chromosomal DNA altering the expression of any one of several silent pilin genes [3]. By doing so, phase variation (pi + to pil-) occurs when the rearrangement involves a defective pilin gene or to avoid their host cell (humans) immune system [1,3]. The tight junctions and adherence to the host cell is due by the Opa proteins. The bacterium, like N. meningitidis, is also naturally competent for DNA uptake after attachment [4].
Aelius Galenus, a Roman physician and philosopher, first observed the bacterium in the second century and loosely named it the "flow of seed" [18]. The term resurfaced in the sixth century when Aetius Amidenus, a Byzantine physician and medical writer, observed the bacterium in pelvic abscesses. Infectiously spreading to France, the term gained popularity as it became symptomatically renown as "La chaude pisse", which literally translates to "hot piss". Finally, in 1879, Albert Ludwig Sigesmund Neisser, a German physician and bacteriologist, was the first person to describe the bacterium as the causative agent of gonorrhea and officially named the bacterium ''Neisseria gonorrhoeae'' [14].
Since N. gonorrhoeae is a typical gram-negative bacteria, its outer membrane is composed of proteins, phospholipids, and lipopolysaccharides (LPS). The lipopolysaccharide can be distinguished from other typically LPS by its highly-branched basal oligosaccharide structure and the absence of repeating O-antigen subunits. So typically, the neisserial LPS is usually referred to as lipooligosaccharide (LOS). During growth, it releases outer membrane fragments called "blebs" which contains LOS and has a role in pathogenesis when they are spread during an infection [2].
N. gonorrhoeae infect the mucous surfaces that are lined with columnar epithelium cells by the attachment of the bacterium via pili (fimbriae) and the production of lipopolysaccharide endotoxin [1,2]. Due to the fact that the lipopolysaccharide is highly toxic and contains virulence factors in the form of its antiphagocytic capsule which produces IgA proteases, they contribute to the viral infection [2].
N. gonorrhoeae is a fragile organism that is easily susceptible to environmental change conditions including temperature changes, drying, UV light, and such. It is a "fastidious" bacterium that requires blood or hemoglobin and several amino acids and vitamins to nourish in order to grow.  In the laboratory, cultures must be grown at 35-36 degrees in an atmosphere of 3-10% added CO2 [1].


===Statistics===
==Description of the Microbe==


Although a cure exists, statistics show that cases of infection are still on the rise. Today, gonorrhea is one of the leading reported sexually transmitted diseases in adults in the United States. The reoccurring trend of increasing rates of gonorrhea infection can be seen uniformly across regions, states, sex, age, and race/ethnicity. In 2007, 355,991 cases of gonorrhea were reported in the United States. This equates to roughly 118.9 cases per 100,000 people in 2007 [4]. This rate of gonorrhea infection has remained relatively stable the past decade, especially among women. The gonorrhea rate among women was reported at 123.5 and the rate among men was reported at 113.7 cases per 100,000 people in 2007 [4]. In the same year, the gonorrhea rates continue to be the highest among young adults and adolescents; among females in the ages of 15 – 24 and among males between the ages of 20 – 24. The data suggests that gonorrhea is still on the rise and further development of treatment beyond the boundaries of medication is needed.
[[Image:SEM.jpg|frame|A SEM of N. gonorrhoeae that has been outlined in color to show the paired diplococci. Image courtesy of CDC. ]]


==Why is the Disease a Problem in the United States?==
[[Neisseria gonorrhoeae]] (''N. gonorrhoeae'') is a gram-negative diplococcus ranging from 0.6 to 1.0 µm in diameter and is usually identified in pairs with adjacent flattened sides. Its outer membrane is composed of proteins, phospholipids, and lipopolysaccharides (LPS). The ''N. gonorrhoeae'' lipopolysaccharide can be distinguished from other types of LPS by "its highly-branched basal oligosaccharide structure and the absence of repeating O-antigen subunits" [18]. Thus, it is referred to as lipooligosaccharide (LOS). During its growth, ''N. gonorrhoeae'' releases its outer membrane fragments called "blebs" that contain LOS, an endotoxin that plays a primary means in the bacterium's pathogenesis [18]. LOS is involved in infection by attaching to host cells, evading the host's immune system via antigenic variation, damaging tissue, and manifesting bactericidal antibodies [8].
The antigenic variation of ''N. gonorrhoeae'' manifests via rearrangements of its chromosomal DNA by the altering of its expression of any one of the several silent pilin genes it can possibly encode [19]. By doing so, phase variation occurs when the rearrangement involves a defective pilin gene, thus avoiding their host (i.e., humans) immune system [13, 19]. Its fimbriae and antigenic type IV pilus enables the bacterium to move, while the opacity (Opa) proteins provide adherence to host cells. Together, they form tight junctions and are constituted of repeated peptide subunits characterized by both antigenic and phase variations [18]. The bacterium, like ''N. meningitidis'', is also "naturally competent for DNA uptake" after attachment [10].
   
Through such means, ''N. gonorrhoeae'' infects the mucous surfaces that are lined with columnar epithelium cells by the attachment of the bacterium via pili (fimbriae) and the production of lipopolysaccharide endotoxin [13, 18]. Due to the fact that the lipopolysaccharide is highly toxic and contains virulence factors in the form of its antiphagocytic capsule which produces IgA proteases, they contribute to the infection [18]. The bacterium is typically observed inside polymorphonuclear leukocytes (i.e., neutrophils) that become a part of the gonorrhea pustular exudate.


Gonorrhea has been a silent disease in the United States (US) largely because anyone sexually active can be infected. The highest reported rates of infection in the US are among sexually active women and African Americans (CDC). It infects about 20,000 individuals each year. It was not long ago that gonorrhea was a serious concern to the public health like many other major STD or STI such as Syphilis, a top priority of all health organizations. 
Overall, ''N. gonorrhoeae'' is a fragile bacterium that is sensitive to environmental conditions including temperature changes, drying, ultraviolet light, and the such. It is a "fastidious" bacterium that "requires hemoglobin or blood, several amino acids, and vitamins" for nourishment. In the laboratory, cultures must be grown at optimal temperature of 35-36 degrees in an atmosphere of 3-10% carbon dioxide [13].
However, according to the New York Times article by Lawrence K. Altman, Sex Diseases Still Rising; Chlamydia Is Leader, “From 1975 through 1997 the reported rate of gonorrhea dropped 74 percent, then plateau, only to rise the last two years to 358,366 cases in 2006. The actual numbers are estimated at about twice of that.” This issues raises concern in America especially because the American people have had the luxury of healthcare that many third world countries are not capable of receiving.  It is apparent that safe sex practices had been abandoned and thus have resulted in a jump in gonorrhea cases recently.   Another risk factor to consider in America is the disproportionately amount of African-Americans having the higher prevalence than any other ethnic groups.  In comparison 18 to 1 ratio of African Americans to Whites.  “African Americans account for 69 percent of all gonorrhea in this country” (Altman, 21).  Also it is important to note according to the newsletter written in DRUG WEEK on an MMWR Report on Gonorrhea and Chlamydia Incidence among MSM, that gonorrhea or Chlamydia infections can be significant co-factors in the transmission of HIV.  This becomes another issue in America as it is the harbor of many homosexuals living in big cities such as San Francisco, Los Angeles, and New York, that such infections can easily be transmitted to many individuals in a very short amount of time.  Often drug use is the highest in these areas, which can further cause a much higher incidence rate.


===Transmission===
===Transmission===


Gonorrhea, which is caused by the bacterium N. gonorrhoeae, is harbored in warm and moist areas and sexually trasmitted through contact of an infected tissue surface on vaginal, penile, anus, or mouth [3,4]. When left untreated, it can severely effect  the uterus, cervix, and fallopian tubes in women and the urethra in men, potentially leading to sterility [2].  
[[Image:Baby.jpg‎‎|frame|left|Newborn with gonococcal ophthalmia neonatorum caused by a maternally transmitted gonococcal infection. Image courtesy of CDC.]]
In addition to being transmitted sexually, it can be transmitted vertically from an infected, pregnant woman to the baby she is carrying. This infection can reach the offspring through the birth canal of the mother during delivery [4].
 
[[Image:Penis.jpg‎|thumb|A purulent penile discharge from gonorrhea with a penile pyodermal lesion. Image courtesy of CDC.]]
 
Gonorrhea, which is caused by the bacterium ''N. gonorrhoeae'', is harbored in warm, moist areas. It is sexually transmitted through the contact of an infected tissue surface on the vaginal, penile, anal, and/or oral cavity and another susceptible mucosa epithelium surface [17,11]. In addition to being sexually transmitted, gonorrhea infection may also be trasnmitted vertically - from mother to child during delivery [11].


===Symptoms===
===Symptoms===


The symptoms on gonorrhea vary substantially and can be fatal if left untreated. In males, signs of symptoms can appear anywhere from 2 days to 30 days or not appear at all. Symptoms can include a white, yellow, or green discharge from the penis or a burning sensation when urinating. Occasionally, males can also get swollen or painful testicles [3]. Among females, it is common that no symptoms show but when symptoms do show, they are very meek. Female symptoms can include painful or burning urination, vaginal bleeding between periods, and increased vaginal discharge [3]. However, their symptoms are often mistaken for a vaginal or bladder infection. Despite the severity or presence of their symptoms, women with gonorrhea are still at great risk of developing serious complications.  
The overall symptoms of gonorrhea vary substantially between the sexes and can be fatal if left untreated. If sexually active, it is safest to routinely get tested and critical to seek medical attention if any of the following symptoms below are observed. Among males, signs of symptoms can appear anywhere from 2 to 30 days after sexual intercourse, or not at all. Such symptoms may include the following: a white, yellow, or green penal discharge, a burning sensation while urinating, and/or the formation of unusual sores/a rash. Occasionally, males can also get swollen and/or feel pain in their testicular regions. If left untreated, males can develop epididymitis, prostatitis, urethritis, become sterile, and potentially die. Among females, it is common for symptoms to appear meek or asymptomatic. If symptoms are observed, they may include the following: a painful or burning sensation while urinating, vaginal bleeding between periods, and increasing vaginal discharge. If left untreated, females may than develop pelvic inflammatory disease, potentially become sterile, and die [5].
 
==Why is the Microbe a Problem in the United States?==
 
A myriad of factors are responsible for the perpetuation of gonorrhea in the United States. Such sources revolve around cultural and socioeconomic determinants. These include but are not limited to: (1) the development of teenage culture prevalent today that stemmed from the 1960's and fosters the risky behavior among teens (i.e., the partaking in drinking, drug use, and promiscuity), (2) the rise of sexual liberalism prevalent today that stemmed from the 1970's sexual revolution [7], (3) the "just world" belief that bad things do not happen to good people, (4) safe sex practices being neglected, (5) no honest, open dialogue among sex partners and their present sexual health, (6) no commitment/no access to regular check-up's [16], (7) denial of diagnosis, (8) increase use of sexual performance drugs in society, (9) diagnosed/asymptomatic individuals partaking in sexual relations before cured and concurrently reinfecting, (10) the increase in population density, especially in metropolitan areas, thereby contributing to an increases in social interaction, networks, and sexual relationships, as well as (11) the limited types of antibiotics available to treat gonorrhea. 
 
Due to all of the above, according to the New York Times article written by Lawrence K. Altman titled, ''Sex Diseases Still Rising: Chlamydia Is Leader'', gonorrhea infections have been on the rise, particularly among sexually active women under the age of twenty five and African American men [1].
 
[[Image:GonorrheaRates07.JPG‎|frame|center|Rates by county of gonorrhea infection in the US. 2007.]]


===Prevention===
==What is Being Done to Combat the Spread of ''N. Gonorrhoeae''?==


According to the CDC fact sheet, the best method for prevention is to abstain from sexual intercourse or to be in a long monogamous relationship with a partner that has been tested or treated for Gonorrhea. Other preventive measures include using latex condoms that can reduce risk of catching such STD.  It is important to seek a doctor if any symptoms such as discharge or burning during urination or unusual sores or rash arise. Most importantly it is essential that to further spread such a disease those individuals that have been diagnosed to notify all previous partners to get tested immediately and to further prevent a serious outbreak of infections. It is also essential to get a routine screening for any groups at risk to constantly be aware of there medical history and condition before they engage in any high risk activity.
As the second most commonly reported sexually transmitted disease, a multitude of prevention and treatment strategies have been developed and enforced to control the spread of gonorrhea. Due to the fact that the prevalence of ''N. gonorrhoeae'' infection varies among communities and populations [4], the basic sociological measures for control include preventative solutions such as: (1) increasing the education and awareness of the ''N. gonorrhoeae'' microbe and its resulting gonorrhea infection, (2) openly supporting abstinence, monogamous relationships [13], and condom use, (3) encouraging those at-risk be tested, (4) stressing the urgency in seeking treatment if diagnosed and refraining from sexual intercourse until remission, and (5) referring the sex partner of the diagnosed be tested [7]. At the clinical front, physicians are doing their part to control ''N. gonorrhoeae'' transmission by testing all at-risk groups – the highest at-risk groups being sexually active women under the age of twenty-five and African American men [3]. Other risk factors include previous gonorrheal infection, diagnosis of other sexually transmitted diseases, new or multiple partners, inconsistent-to-no condom use, commercial sex work, as well as drug use. The effective diagnostic tests at which physicians are currently utilizing to test for ''N. gonorrhoeae'' include: Gram stain (reserved for symptomatic patients only), culture, nucleic acid hybridization tests, and nucleic acid amplification tests (NAAT). Each requires the testing of cervical, vaginal, male urethral, and/or urine specimens. Fortunately, if a positive test for ''N. gonorrhoeae'' results, due to the fact that the microbe is a bacterium, it can easily be treated and cured with antibiotics such as ceftriaxone, cefixime, ciprofloxacin, ofloxacin, or levofloxacin. However, with ''N. gonorrhoeae''’s rising co-infection with uncomplicated ''C. trachomatis'' and health officials’ routine approach to co-treat both bacterial infections, an antimicrobial-resistant ''N. gonorrhoeae'' strain known as quinolone-resistant ''N. gonorrhoeae'' (QRNG) has developed.  As a result, common antidotes containing fluoroquinolones, such as ciprofloxacin, are inadvisable, especially in the United States. Two states of particular concern are California and Hawaii as they both contain the highest prevalence of QRNG as seen in the Centers for Disease Control and Prevention’s Gonococcal Isolate Surveillance Project 2004 study of 6,322 isolates showing 6.8% resistant to ciprofloxacin. Excluding the isolates gathered from California and Hawaii, only 3.6% were QRNG [4]. Overall, this study’s conclusion is critical as it highlights the competitive race between aggressively adapting antibiotic-resistant microbes and the scientific discovery of new antibiotics.
Furthermore due to the development of resistance in Neisseria gonorrhea to the many antimicrobial classes brings a much needed challenge to the control of gonorrhea. Another unique prevention strategy implemented enhancement of national and international surveillance, to monitor resistance and to better compliment new strategies to essentially maximize the benefit and further prolong the utility of antimicrobials. This can include combination regimens, applying screening recommendations for those that are high risk for infection, and to further continue proper effective treatment for infected persons and their sexual partners. Testing every 3 to 4 months after treatment for initial infection is highly recommended to prevent re-infection.
An article in Drug Week published March 20, 2009 tried to identify intervention strategies for prevention and control in San Francisco, found that there was a substantial gonorrhea increase among young heterosexuals during 2003-2005.  The researchers concluded based on there case study that “Prevention and control efforts are focusing on blacks and incarcerated populations using street-based outreach and expanded screening and treatment.” (Barry, 616).


==What is Being Done to Combat the Spread of N. Gonorrhoeae?==
==What Else Can be Done to Address this Rising Problem?==


According to the Centers for Disease Control and Prevention’s Morbidity and Mortality Weekly Report Sexually Transmitted Diseases Treatment Guidelines, 2006, approximately 600,000 new infections of N. gonorrhoeae occur each year in the United States. As the second most commonly reported sexually transmitted disease, a multitude of prevention and treatment strategies have been developed and enforced to control its spread. Due to the fact that the prevalence of N. gonorrhoeae infection varies among communities and populations [1], the basic sociological measures of control include preventative solutions such as: (1) increasing the education and awareness of the N. gonorrhoeae microbe and its resulting gonorrhea infection, (2) openly supporting condom use, (3) encouraging those at-risk be tested, (4) stressing the urgency in seeking treatment if diagnosed and refraining from sexual intercourse until remission, and (5) referring the diagnosed sex partner(s) be tested [2].
As antibiotic-resistant strands of ''N. gonorrhoeae'' continue to spread throughout the United States, certain antibiotics are increasingly becoming ineffective in treating gonorrhea. Since 1993, fluoroquinones have been used frequently to treat gonorrhea in the United States because it was the overall drug treatment of choice; fluoroquinones were effective as an easy oral method of treatment that required only a single dose. In 2006, however, the Centers for Disease Control and Prevention (CDC) announced that it no longer recommends fluoroquinones for treatment of gonorrhea because of the bacterium's increasing resistance throughout the United States. Similarly, other antibiotics such as penicillin, tetracycline, and macrolides have not been recommended in the United States because susceptibility to such drugs has been inadequate [5]. Currently, drugs within the cephalosporin class are being used to treat gonorrhea in the United States, but growing resistance and adaptation to antibiotics places heavy emphasis on the development of novel pharmaceuticals for future treatment of gonorrhea. Current research seeks to uncover the genetic and molecular specifics of ''N. gonorrhoeae'', such that particular drugs may be targeted to disrupt it. For example, antigenic variation has been found in ''N. gonorrhoeae'', thus making it hard to develop a vaccine against it [14]. Thus, more focused, pharmaceutical studies geared toward uncovering the molecular basis by which antigenic variation occurs would prove itself useful for combating antibiotic-resistant strands of ''N. gonorrhoeae'' [16].
At the clinical front, physicians are doing their part to control N. gonorrhoeae transmission by testing all at-risk groups – the highest at-risk group being sexually active women under the age of twenty-five. Other risk factors include previous gonorrhea infection, diagnosis of other sexually transmitted diseases, new or multiple partners, inconsistent-to-no condom use, commercial sex work, as well as drug use. The effective diagnostic tests at which physicians are currently utilizing to test for N. gonorrhoeae include: Gram stain (reserved for symptomatic patients only), culture, nucleic acid hybridization tests, and nucleic acid amplification tests (NAAT). Each requires the testing of cervical, vaginal, male urethral, and/or urine specimens. Fortunately, if a positive test for N. gonorrhoeae results, due to the fact that the microbe is a bacterium, it can easily be treated and cured with antibiotics such as ceftriaxone, cefixime, ciprofloxacin, ofloxacin, or levofloxacin. However, with N. gonorrhoeae’s rising co-infection with uncomplicated C. trachomatis and health officials’ routine approach to co-treat both bacterial infections, an antimicrobial-resistant N. gonorrhoeae strain known as quinolone-resistant N. gonorrhoeae (QRNG) has developed.  As a result, common antidotes containing quinolones, such as ciprofloxacin, are inadvisable, especially in the United States. Two states of particular concern are California and Hawaii as they both contain the highest prevalence of QRNG as seen  in the Centers for Disease Control and Prevention’s Gonococcal Isolate Surveillance Project 2004 study of 6,322 isolates showing 6.8% resistant to ciprofloxacin. Excluding the isolates gathered from California and Hawaii, only 3.6% were QRNG [1]. Overall, this study’s conclusion is critical as it highlights the competition between aggressively adapting antibiotic-resistant microbes and the scientific discovery of new antibiotics.


==What Else Could be Done to Address this Problem?==
Along with the development of novel drugs for treatment, the development of novel techniques to diagnose individuals with gonorrhea would also be effective toward curbing the spread of the infection. One such recently developed technique that has gained the respect of being the most sensitive and specific test to date for ''N. gonorrhoeae'' detection is the nucleic acid amplification test (NAAT)— of which polymerase chain reaction (PCR) falls into categorically. Despite the effectiveness of NAAT, the Food and Drug Administration (FDA) has not cleared for its use on rectal and pharyngeal tissues [3] due to the fact that native microbes that inhabit those areas compromise test results. Future developments may empirically test NAAT to ascertain its usefulness for diagnosing such areas, thereby lifting the FDA restriction.


As antibiotic-resistant strands of N. gonorrhoeae continue to spread throughout the United States, certain antibiotics are increasingly becoming ineffective in treating gonorrhea. Since 1993, fluoroquinones have been used frequently to treat gonorrhea in the United States because it was the overall drug treatment of choice; fluoroquinones were effective as an oral mode of treatment that required only one dose. By 2006, the Center for Disease Control and Prevention (CDC) announced that it no longer recommends fluoroquinones for treatment of gonorrhea because of increasing resistance throughout the United States. Similarly, other antibiotics such as penicillin, tetracycline, and macrolides have not been recommended in the United States because susceptibility to such drugs has been inadequate [1]. Currently, drugs within the cephalosporin class are being used to treat gonorrhea in the United States, but growing resistance and adaptation to antibiotics places heavy emphasis on the development of novel pharmaceuticals for future treatment of gonorrhea. Current research seeks to uncover the genetic and molecular specifics of N. gonorrhoeae, such that particular drugs may be targeted to disrupt it. For example, antigenic variation has been found in N. gonorrhoeae, thus making it hard to develop a vaccine against it [2]. A more recent study has uncovered the molecular basis by which antigenic variation occurs, such that the newly acquired insight may be useful for ongoing pharmaceutical developments against N. gonorrhoeae [3].
Another mode for preventing further spread of gonorrhea is through the development of more hubs for disease control (e.g., clinics), particularly in metropolitan areas where infection is most prevalent due to high population density and increased social and sexual interaction. By constructing more clinics, a more accurate representation of the epidemiology of ''N. gonorrhoeae'' may be ascertained. The means by which the United States currently monitors and controls ''N. gonorrhoeae'' epidemiology is through the Gonococcal Isolate Surveillance Project (GISP). GISP monitors ''N. gonorrhoeae'' prevalence and its susceptibility to antibiotics through sexually-transmitted disease (STD) clinics, regional laboratories, and the CDC itself. It was through GISP that resistance to a fluoroquinone was first identified in 1991. In GISP protocol, a representative subset of the cultures positive for ''N. gonorrhoeae'' are tested for antibiotic resistance. As a result, specific antibiotics are prescribed based on demographic and regional data such that treatment remains effective. Currently, approximately 28 cities with STD clinics are part of GISP. With more hubs of disease control, the accessibility of preventative education, materials, and treatment would become available to better tailor to regional needs [2].


Along with novel drugs for treatment, there can also be novel techniques to diagnose individuals with gonorrhea. One such recently developed technique that has been known as the most sensitive and specific test to date for N. gonorrhoeae detection is the nucleic acid amplification test (NAAT)—of which polymerase chain reaction (PCR) falls into categorically. Despite NAAT qualifications, the food and drug administration (FDA) has not cleared the use of such a nonculture test for testing in the rectum and pharynx [4]. Future developments may empirically test the NAAT to ascertain its usefulness for diagnosing such areas, thereby lifting the FDA restriction.
==Conclusion==


Another mode for preventing further spread of gonorrhea is through the development of more hubs of disease control (e.g., clinics), particularly in metropolitan areas. By constructing more clinics, a more accurate representation of the epidemiology of N. gonorrhoeae may be ascertained. The means by which the United States currently monitors and controls N. gonorrhoeae epidemiology is through the Gonococcal Isolate Surveillance Project (GISP). GISP monitors N. gonorrhoeae prevalence and its susceptibility to antibiotics through sexually-transmitted disease (STD) clinics, regional laboratories, and the CDC itself. It was through GISP that resistance to a fluoroquinone was first identified in 1991. In GISP protocol, a representative subset of the cultures positive for N. gonorrhoeae are tested for antibiotic resistance. As a result, specific antibiotics are prescribed based on demographic and regional data such that treatment remains effective. Currently, approximately 28 cities with STD clinics are part of GISP. With more hubs of disease control, prevention and treatment may be better tailored to regional needs [5].
With the advancement of diagnosis and treatment for gonorrhea along with the historical understanding of the microbe known as Neisseria gonorrhoeae, there is now an awareness of the spread of this microbe through sexual contact producing environments conducive to its multiplication. The discovery, development, transmission, and analysis of tactics to preventing this microbe from spreading have made strides in science as the topic of sexual intercourse becomes an everyday topic. This problem of gonorrhea is still prevalent in the United States and in order to improve and find better means of prevention, further studies are being conducted to learn more about this sexually transmitted microbe and the people that it affects.


==References==
==References==
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1. Altman, Lawrence K. "Sex Diseases Still Rising; Chlamydia Is Leader." The New York Times 14 Nov. 2007: 21-21. Print.
 
2. [http://www.cdc.gov/std/GISP2007/GISPSurvSupp2007Short.pdf Center for Disease Control and Prevention. Gonococcal Isolate Surveillance Project (GISP): Annual Report 2007. March 2009.]
 
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5. [http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5614a3.htm Center for Disease Control and Prevention. Update to CDC’s sexually transmitted diseases treatment guidelines, 2006: Fluoroquinones no longer recommended for treatment of gonococcal infections. MMWR 2007; 56(14): 332-336.]
 
6. Chesson, Harrell W., Akbar A. Zaidi, and Sevgi O. Aral. "Decreasing Age Disparities in Syphilis and Gonorrhea in Incidence Rates in the United States, 1981-2005." Sexually Transmitted Diseases. American Sexually Transmitted Diseases Association, Apr. 2008. Web. 28 Aug. 2009. Vol. 35, No. 4, p.393–397
 
7. Crosby, R.A., R.J. DiClement, S.L. Rosenthal, and L.F. Salazar. Prevention and Control of Sexually Transmitted Infections Among Adolescents: The Importance of a Socio-Ecological Perspective. ScienceDirect 2005; 119.9:825-36. Print.
 
8. [http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=177611&blobtype=pdf Danaher, Robert J., James C. Levin, Dan Arking, Christina L. Burch, Robin Sandlin, and Daniel C. Stein. "Genetic Basic of Neisseria Gonorrhoeae Lipooligosaccharide Antigenic Variation." PubMed Central. American Society for Microbiology, Dec. 1995. Web. 27 Aug. 2009.]
 
9. [http://www.annals.org/cgi/content/full/148/8/606 "Emerging Antimicrobial Resistance in Neisseria gonorrhea: Urgent Need to Strengthen Prevention Strategies -- Workowski et al. 148 (8): 606 -- Annals of Internal Medicine." Annals of Internal Medicine - Home. Web. 26 Aug. 2009.]
 
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12. [http://www.cdc.gov/std/gonorrhea/#fact "Gonorrhea - STD information from CDC." Centers for Disease Control and Prevention. Web. 26 Aug. 2009.]
 
13. [http://bioinfo.bact.wisc.edu/themicrobialworld/Gonorrhea.html "Gonorrhea." Welcome to the UW-Madison Dept. of Bacteriology. Web. 26 Aug. 2009.]
 
14. Hedges SR, Mayo MS, Mestecky J, Hook EW III & Russell MW (1999) Limited Local and Systemic Antibody Responses to Neisseria Gonorrhoeae During Uncomplicated Genital Infections. Infect Immun 67: 3937–3946. Print.
 
16. Newman, Lori M., and Stuart M. Berman. "Epidemiology of STD Disparities in African American Communities." Sexually Transmitted Diseases. American Sexually Transmitted Diseases Association, Dec. 2008. Web. 28 Aug. 2009. Vol. 35, No. 12, p.S4–S12
 
15. O'Dowd, Michael J. The History of Medications for Women. New York City: The Parthenon Publishing Group Inc., 2001. Print.
 
16. Pilin Gene Variation in Neisseria Gonorrhoeae: Reassessing the Old Paradigms. FEMS Microbiology Reviews [0168-6445]  Hill, Stuart  (2009)  volume: 33  issue: 3  page: 521 -30. Print.
 
17. [http://www.cdc.gov/std/gonorrhea/STDFact-gonorrhea.htm#How "STD Facts - Gonorrhea." Centers for Disease Control and Prevention. Web. 26 Aug. 2009.]
 
18. [http://textbookofbacteriology.net/neisseria.html Todar, Kenneth. “Pathogenic Neisseriae: Gonorrhea, neonatal Opthalmia and Meningococcal Meningitis.” Todar’s Online Textbook of Baceriology. 2008. 23 Aug 2008.]
 
19. [http://www.who.int/vaccine_research/diseases/soa_std/en/index2.html "WHO | Sexually Transmitted Diseases." Web. 25 Aug. 2009.]
 
 
 


Edited by [Joelle Abed Elahad, Mykel Anderson, Cuong Nguyen, Fisal Mohsini, Danny Huynh, Tim Chiang], students of [mailto:ralarsen@ucsd.edu Rachel Larsen]
Edited by: Joelle Abed Elahad, Mykel Anderson, Tim Chiang, Danny Huynh, Fisal Mohsini, and Cuong Nguyen, students of [mailto:ralarsen@ucsd.edu Rachel Larsen], Ph.D.

Latest revision as of 03:19, 20 August 2010

This student page has not been curated.
Gram-stain of a urethral exudate that is diagnostic of gonococcal urethritis. Image courtesy of CDC.



Introduction

Albert Ludwig Sigesmund Neisser, discoverer of the pathogen N. gonorrhoeae.

With over 600,000 new infections reported each year, Neisseria gonorrhoeae (N. gonorrhoeae) has become the second most common, sexually transmitted infection in the United States. With its incidence only second to Chlamydia trachomatisa [5], the most disturbing fact of N. gonorrhoeae lies in the reality that it shows no discrimination among the sexually active - anyone and everyone is susceptible. The group most at-risk are sexually active women under the age of twenty-five and African American men [3]. Other risk factors include previous gonorrheal infection, diagnosis of other sexually transmitted diseases, new or multiple partners, inconsistent-to-no condom use, commercial sex work, as well as drug use [5]. Notable symptoms in males may include swollen and painfully sensitive testes, a white, yellow, or green penal discharge, a burning sensation while urinating, and/or the formation of unusual sores/a rash. In females, symptoms may include a painful or burning sensation while urinating, vaginal bleeding between periods, and/or increasing vaginal discharge. Due to the fact that the majority of those infected are asymptomatic, especially among women, if left untreated, the infection can result in the sterility in either sexes and in extreme cases, lead to their fatality [5]. Thus, the only factor keeping the infection from developing into an epidemic rests upon people routinely getting tested. Fortunately, because N. gonorrhoeae is a bacterium, curable treatment is available. However, this relief is currently being threatened.

History of the Name Neisseria Gonorrhoeae (N. Gonorrhoeae)

Aelius Galenus, a Roman physician and philosopher, first observed the bacterium in the second century and loosely named it the "flow of seed" [18]. The term resurfaced in the sixth century when Aetius Amidenus, a Byzantine physician and medical writer, observed the bacterium in pelvic abscesses. Infectiously spreading to France, the term gained popularity as it became symptomatically renown as "La chaude pisse", which literally translates to "hot piss". Finally, in 1879, Albert Ludwig Sigesmund Neisser, a German physician and bacteriologist, was the first person to describe the bacterium as the causative agent of gonorrhea and officially named the bacterium Neisseria gonorrhoeae [14].

Description of the Microbe

A SEM of N. gonorrhoeae that has been outlined in color to show the paired diplococci. Image courtesy of CDC.

Neisseria gonorrhoeae (N. gonorrhoeae) is a gram-negative diplococcus ranging from 0.6 to 1.0 µm in diameter and is usually identified in pairs with adjacent flattened sides. Its outer membrane is composed of proteins, phospholipids, and lipopolysaccharides (LPS). The N. gonorrhoeae lipopolysaccharide can be distinguished from other types of LPS by "its highly-branched basal oligosaccharide structure and the absence of repeating O-antigen subunits" [18]. Thus, it is referred to as lipooligosaccharide (LOS). During its growth, N. gonorrhoeae releases its outer membrane fragments called "blebs" that contain LOS, an endotoxin that plays a primary means in the bacterium's pathogenesis [18]. LOS is involved in infection by attaching to host cells, evading the host's immune system via antigenic variation, damaging tissue, and manifesting bactericidal antibodies [8].

The antigenic variation of N. gonorrhoeae manifests via rearrangements of its chromosomal DNA by the altering of its expression of any one of the several silent pilin genes it can possibly encode [19]. By doing so, phase variation occurs when the rearrangement involves a defective pilin gene, thus avoiding their host (i.e., humans) immune system [13, 19]. Its fimbriae and antigenic type IV pilus enables the bacterium to move, while the opacity (Opa) proteins provide adherence to host cells. Together, they form tight junctions and are constituted of repeated peptide subunits characterized by both antigenic and phase variations [18]. The bacterium, like N. meningitidis, is also "naturally competent for DNA uptake" after attachment [10].

Through such means, N. gonorrhoeae infects the mucous surfaces that are lined with columnar epithelium cells by the attachment of the bacterium via pili (fimbriae) and the production of lipopolysaccharide endotoxin [13, 18]. Due to the fact that the lipopolysaccharide is highly toxic and contains virulence factors in the form of its antiphagocytic capsule which produces IgA proteases, they contribute to the infection [18]. The bacterium is typically observed inside polymorphonuclear leukocytes (i.e., neutrophils) that become a part of the gonorrhea pustular exudate.

Overall, N. gonorrhoeae is a fragile bacterium that is sensitive to environmental conditions including temperature changes, drying, ultraviolet light, and the such. It is a "fastidious" bacterium that "requires hemoglobin or blood, several amino acids, and vitamins" for nourishment. In the laboratory, cultures must be grown at optimal temperature of 35-36 degrees in an atmosphere of 3-10% carbon dioxide [13].

Transmission

Newborn with gonococcal ophthalmia neonatorum caused by a maternally transmitted gonococcal infection. Image courtesy of CDC.
A purulent penile discharge from gonorrhea with a penile pyodermal lesion. Image courtesy of CDC.

Gonorrhea, which is caused by the bacterium N. gonorrhoeae, is harbored in warm, moist areas. It is sexually transmitted through the contact of an infected tissue surface on the vaginal, penile, anal, and/or oral cavity and another susceptible mucosa epithelium surface [17,11]. In addition to being sexually transmitted, gonorrhea infection may also be trasnmitted vertically - from mother to child during delivery [11].

Symptoms

The overall symptoms of gonorrhea vary substantially between the sexes and can be fatal if left untreated. If sexually active, it is safest to routinely get tested and critical to seek medical attention if any of the following symptoms below are observed. Among males, signs of symptoms can appear anywhere from 2 to 30 days after sexual intercourse, or not at all. Such symptoms may include the following: a white, yellow, or green penal discharge, a burning sensation while urinating, and/or the formation of unusual sores/a rash. Occasionally, males can also get swollen and/or feel pain in their testicular regions. If left untreated, males can develop epididymitis, prostatitis, urethritis, become sterile, and potentially die. Among females, it is common for symptoms to appear meek or asymptomatic. If symptoms are observed, they may include the following: a painful or burning sensation while urinating, vaginal bleeding between periods, and increasing vaginal discharge. If left untreated, females may than develop pelvic inflammatory disease, potentially become sterile, and die [5].

Why is the Microbe a Problem in the United States?

A myriad of factors are responsible for the perpetuation of gonorrhea in the United States. Such sources revolve around cultural and socioeconomic determinants. These include but are not limited to: (1) the development of teenage culture prevalent today that stemmed from the 1960's and fosters the risky behavior among teens (i.e., the partaking in drinking, drug use, and promiscuity), (2) the rise of sexual liberalism prevalent today that stemmed from the 1970's sexual revolution [7], (3) the "just world" belief that bad things do not happen to good people, (4) safe sex practices being neglected, (5) no honest, open dialogue among sex partners and their present sexual health, (6) no commitment/no access to regular check-up's [16], (7) denial of diagnosis, (8) increase use of sexual performance drugs in society, (9) diagnosed/asymptomatic individuals partaking in sexual relations before cured and concurrently reinfecting, (10) the increase in population density, especially in metropolitan areas, thereby contributing to an increases in social interaction, networks, and sexual relationships, as well as (11) the limited types of antibiotics available to treat gonorrhea.

Due to all of the above, according to the New York Times article written by Lawrence K. Altman titled, Sex Diseases Still Rising: Chlamydia Is Leader, gonorrhea infections have been on the rise, particularly among sexually active women under the age of twenty five and African American men [1].

Rates by county of gonorrhea infection in the US. 2007.

What is Being Done to Combat the Spread of N. Gonorrhoeae?

As the second most commonly reported sexually transmitted disease, a multitude of prevention and treatment strategies have been developed and enforced to control the spread of gonorrhea. Due to the fact that the prevalence of N. gonorrhoeae infection varies among communities and populations [4], the basic sociological measures for control include preventative solutions such as: (1) increasing the education and awareness of the N. gonorrhoeae microbe and its resulting gonorrhea infection, (2) openly supporting abstinence, monogamous relationships [13], and condom use, (3) encouraging those at-risk be tested, (4) stressing the urgency in seeking treatment if diagnosed and refraining from sexual intercourse until remission, and (5) referring the sex partner of the diagnosed be tested [7]. At the clinical front, physicians are doing their part to control N. gonorrhoeae transmission by testing all at-risk groups – the highest at-risk groups being sexually active women under the age of twenty-five and African American men [3]. Other risk factors include previous gonorrheal infection, diagnosis of other sexually transmitted diseases, new or multiple partners, inconsistent-to-no condom use, commercial sex work, as well as drug use. The effective diagnostic tests at which physicians are currently utilizing to test for N. gonorrhoeae include: Gram stain (reserved for symptomatic patients only), culture, nucleic acid hybridization tests, and nucleic acid amplification tests (NAAT). Each requires the testing of cervical, vaginal, male urethral, and/or urine specimens. Fortunately, if a positive test for N. gonorrhoeae results, due to the fact that the microbe is a bacterium, it can easily be treated and cured with antibiotics such as ceftriaxone, cefixime, ciprofloxacin, ofloxacin, or levofloxacin. However, with N. gonorrhoeae’s rising co-infection with uncomplicated C. trachomatis and health officials’ routine approach to co-treat both bacterial infections, an antimicrobial-resistant N. gonorrhoeae strain known as quinolone-resistant N. gonorrhoeae (QRNG) has developed. As a result, common antidotes containing fluoroquinolones, such as ciprofloxacin, are inadvisable, especially in the United States. Two states of particular concern are California and Hawaii as they both contain the highest prevalence of QRNG as seen in the Centers for Disease Control and Prevention’s Gonococcal Isolate Surveillance Project 2004 study of 6,322 isolates showing 6.8% resistant to ciprofloxacin. Excluding the isolates gathered from California and Hawaii, only 3.6% were QRNG [4]. Overall, this study’s conclusion is critical as it highlights the competitive race between aggressively adapting antibiotic-resistant microbes and the scientific discovery of new antibiotics.

What Else Can be Done to Address this Rising Problem?

As antibiotic-resistant strands of N. gonorrhoeae continue to spread throughout the United States, certain antibiotics are increasingly becoming ineffective in treating gonorrhea. Since 1993, fluoroquinones have been used frequently to treat gonorrhea in the United States because it was the overall drug treatment of choice; fluoroquinones were effective as an easy oral method of treatment that required only a single dose. In 2006, however, the Centers for Disease Control and Prevention (CDC) announced that it no longer recommends fluoroquinones for treatment of gonorrhea because of the bacterium's increasing resistance throughout the United States. Similarly, other antibiotics such as penicillin, tetracycline, and macrolides have not been recommended in the United States because susceptibility to such drugs has been inadequate [5]. Currently, drugs within the cephalosporin class are being used to treat gonorrhea in the United States, but growing resistance and adaptation to antibiotics places heavy emphasis on the development of novel pharmaceuticals for future treatment of gonorrhea. Current research seeks to uncover the genetic and molecular specifics of N. gonorrhoeae, such that particular drugs may be targeted to disrupt it. For example, antigenic variation has been found in N. gonorrhoeae, thus making it hard to develop a vaccine against it [14]. Thus, more focused, pharmaceutical studies geared toward uncovering the molecular basis by which antigenic variation occurs would prove itself useful for combating antibiotic-resistant strands of N. gonorrhoeae [16].

Along with the development of novel drugs for treatment, the development of novel techniques to diagnose individuals with gonorrhea would also be effective toward curbing the spread of the infection. One such recently developed technique that has gained the respect of being the most sensitive and specific test to date for N. gonorrhoeae detection is the nucleic acid amplification test (NAAT)— of which polymerase chain reaction (PCR) falls into categorically. Despite the effectiveness of NAAT, the Food and Drug Administration (FDA) has not cleared for its use on rectal and pharyngeal tissues [3] due to the fact that native microbes that inhabit those areas compromise test results. Future developments may empirically test NAAT to ascertain its usefulness for diagnosing such areas, thereby lifting the FDA restriction.

Another mode for preventing further spread of gonorrhea is through the development of more hubs for disease control (e.g., clinics), particularly in metropolitan areas where infection is most prevalent due to high population density and increased social and sexual interaction. By constructing more clinics, a more accurate representation of the epidemiology of N. gonorrhoeae may be ascertained. The means by which the United States currently monitors and controls N. gonorrhoeae epidemiology is through the Gonococcal Isolate Surveillance Project (GISP). GISP monitors N. gonorrhoeae prevalence and its susceptibility to antibiotics through sexually-transmitted disease (STD) clinics, regional laboratories, and the CDC itself. It was through GISP that resistance to a fluoroquinone was first identified in 1991. In GISP protocol, a representative subset of the cultures positive for N. gonorrhoeae are tested for antibiotic resistance. As a result, specific antibiotics are prescribed based on demographic and regional data such that treatment remains effective. Currently, approximately 28 cities with STD clinics are part of GISP. With more hubs of disease control, the accessibility of preventative education, materials, and treatment would become available to better tailor to regional needs [2].

Conclusion

With the advancement of diagnosis and treatment for gonorrhea along with the historical understanding of the microbe known as Neisseria gonorrhoeae, there is now an awareness of the spread of this microbe through sexual contact producing environments conducive to its multiplication. The discovery, development, transmission, and analysis of tactics to preventing this microbe from spreading have made strides in science as the topic of sexual intercourse becomes an everyday topic. This problem of gonorrhea is still prevalent in the United States and in order to improve and find better means of prevention, further studies are being conducted to learn more about this sexually transmitted microbe and the people that it affects.

References

1. Altman, Lawrence K. "Sex Diseases Still Rising; Chlamydia Is Leader." The New York Times 14 Nov. 2007: 21-21. Print.

2. Center for Disease Control and Prevention. Gonococcal Isolate Surveillance Project (GISP): Annual Report 2007. March 2009.

3. Centers for Disease Control and Prevention. Sexually Transmitted Diseases Surveillance, 2007. MMWR 2007; 55 (No. RR-11).

4. Center for Disease Control and Prevention. Sexually Transmitted Diseases Treatment Guidelines, 2006. MMWR 2006; 55 (No. RR-11):42-55.

5. Center for Disease Control and Prevention. Update to CDC’s sexually transmitted diseases treatment guidelines, 2006: Fluoroquinones no longer recommended for treatment of gonococcal infections. MMWR 2007; 56(14): 332-336.

6. Chesson, Harrell W., Akbar A. Zaidi, and Sevgi O. Aral. "Decreasing Age Disparities in Syphilis and Gonorrhea in Incidence Rates in the United States, 1981-2005." Sexually Transmitted Diseases. American Sexually Transmitted Diseases Association, Apr. 2008. Web. 28 Aug. 2009. Vol. 35, No. 4, p.393–397

7. Crosby, R.A., R.J. DiClement, S.L. Rosenthal, and L.F. Salazar. Prevention and Control of Sexually Transmitted Infections Among Adolescents: The Importance of a Socio-Ecological Perspective. ScienceDirect 2005; 119.9:825-36. Print.

8. Danaher, Robert J., James C. Levin, Dan Arking, Christina L. Burch, Robin Sandlin, and Daniel C. Stein. "Genetic Basic of Neisseria Gonorrhoeae Lipooligosaccharide Antigenic Variation." PubMed Central. American Society for Microbiology, Dec. 1995. Web. 27 Aug. 2009.

9. "Emerging Antimicrobial Resistance in Neisseria gonorrhea: Urgent Need to Strengthen Prevention Strategies -- Workowski et al. 148 (8): 606 -- Annals of Internal Medicine." Annals of Internal Medicine - Home. Web. 26 Aug. 2009.

10. "Genome Project Result." NCBI HomePage. Web. 25 Aug. 2009.

11. "Gonorrhea." National Institute of Allergy and Infectious Diseases. Web. 26 Aug. 2009.

12. "Gonorrhea - STD information from CDC." Centers for Disease Control and Prevention. Web. 26 Aug. 2009.

13. "Gonorrhea." Welcome to the UW-Madison Dept. of Bacteriology. Web. 26 Aug. 2009.

14. Hedges SR, Mayo MS, Mestecky J, Hook EW III & Russell MW (1999) Limited Local and Systemic Antibody Responses to Neisseria Gonorrhoeae During Uncomplicated Genital Infections. Infect Immun 67: 3937–3946. Print.

16. Newman, Lori M., and Stuart M. Berman. "Epidemiology of STD Disparities in African American Communities." Sexually Transmitted Diseases. American Sexually Transmitted Diseases Association, Dec. 2008. Web. 28 Aug. 2009. Vol. 35, No. 12, p.S4–S12

15. O'Dowd, Michael J. The History of Medications for Women. New York City: The Parthenon Publishing Group Inc., 2001. Print.

16. Pilin Gene Variation in Neisseria Gonorrhoeae: Reassessing the Old Paradigms. FEMS Microbiology Reviews [0168-6445] Hill, Stuart (2009) volume: 33 issue: 3 page: 521 -30. Print.

17. "STD Facts - Gonorrhea." Centers for Disease Control and Prevention. Web. 26 Aug. 2009.

18. Todar, Kenneth. “Pathogenic Neisseriae: Gonorrhea, neonatal Opthalmia and Meningococcal Meningitis.” Todar’s Online Textbook of Baceriology. 2008. 23 Aug 2008.

19. "WHO | Sexually Transmitted Diseases." Web. 25 Aug. 2009.



Edited by: Joelle Abed Elahad, Mykel Anderson, Tim Chiang, Danny Huynh, Fisal Mohsini, and Cuong Nguyen, students of Rachel Larsen, Ph.D.

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