Editing Neisseria gonorrhoeae (section)

== Disease ==
{{main|Gonorrhoea}}

=== Symptoms ===
Symptoms of infection with ''N. gonorrhoeae'' differ depending on the site of infection and many infections are asymptomatic independent of sex.<ref>{{cite journal | vauthors = Detels R, Green AM, Klausner JD, Katzenstein D, Gaydos C, Handsfield H, Pequegnat W, Mayer K, Hartwell TD, Quinn TC | title = The incidence and correlates of symptomatic and asymptomatic Chlamydia trachomatis and Neisseria gonorrhoeae infections in selected populations in five countries | journal = Sexually Transmitted Diseases | volume = 38 | issue = 6 | pages = 503–509 | date = June 2011 | pmid = 22256336 | pmc = 3408314 | doi = 10.1097/OLQ.0b013e318206c288 }}</ref><ref name="Edwards_2004" /><ref name="www.cdc.gov_2017">{{Cite web|url=https://www.cdc.gov/std/gonorrhea/stdfact-gonorrhea-detailed.htm|title=Detailed STD Facts - Gonorrhea|date=2017-09-26|website=www.cdc.gov|language=en-us|access-date=2017-12-07}}</ref> Depending on the route of transmission, ''N. gonorrhoeae'' may cause infection of the throat ([[pharyngitis]]) or infection of the anus/rectum ([[proctitis]]).<ref name="Sherris2" /><ref name="Lev13th2" />

Disseminated gonococcal infections can occur when ''N. gonorrhoeae'' enters the bloodstream, often spreading to the joints and causing a rash (dermatitis-arthritis syndrome).<ref name="Sherris2" /> Dermatitis-arthritis syndrome results in joint pain ([[Septic arthritis|arthritis]]), tendon inflammation ([[tenosynovitis]]), and painless non-[[pruritic]] (non-itchy) [[dermatitis]].<ref name="Lev13th2" /> Disseminated infection and pelvic inflammatory disease in women tend to begin after [[Menstruation|menses]] due to reflux during menses, facilitating spread.<ref name="Sherris2" /> In rare cases, disseminated infection may cause infection of the meninges of the brain and spinal cord ([[meningitis]]) or infection of the heart valves ([[endocarditis]]).<ref name="Sherris2" /><ref name="www.cdc.gov" />

==== Male ====
In symptomatic men, the primary symptom of genitourinary infection is urethritis – burning with urination ([[dysuria]]), increased urge to urinate, and a [[pus]]-like (purulent) discharge from the penis. The discharge may be foul smelling.<ref name="Sherris2">{{cite book|url=https://books.google.com/books?id=RRRrAAAAMAAJ|title=Sherris Medical Microbiology|publisher=McGraw Hill|year=2004|isbn=978-0-8385-8529-0| veditors = Ryan KJ, Ray CG |edition=4th }}{{page needed|date=February 2015}}</ref> If untreated, scarring of the [[urethra]] may result in difficulty urinating. Infection may spread from the urethra in the penis to nearby structures, including the testicles ([[epididymitis]]/[[orchitis]]), or to the prostate ([[prostatitis]]).<ref name="Sherris2" /><ref name="Lev13th2">{{cite book | vauthors = Levinson W |title=Review of medical microbiology and immunology |date=2014 |publisher=McGraw-Hill Education |isbn=978-0-07-181811-7 |oclc=871305336 }}{{page needed|date=September 2021}}</ref><ref>{{cite web|url=https://www.std-gov.org/stds/gonorrhea.htm|title=Gonorrhea (the clap) Symptoms|publisher=std-gov.org|date=2015-04-02}}</ref>

==== Female ====
[[File:Neisseria gonorrhoeae and pus cells in a vaginal swab (Gram stain).jpg|thumb|Gram stain of a vaginal swab showing gonococci (in pairs - arrow) inside polymorphonuclear granulocytes]]

In symptomatic women, the primary symptoms of genitourinary infection are increased vaginal discharge, burning with urination ([[dysuria]]), increased urge to urinate, pain with intercourse, or menstrual abnormalities. [[Pelvic inflammatory disease]] results if ''N. gonorrhoeae'' ascends into the pelvic [[peritoneum]] (via the [[cervix]], [[endometrium]], and [[fallopian tubes]]). The resulting inflammation and scarring of the fallopian tubes can lead to infertility and increased risk of ectopic pregnancy.<ref name="Sherris2" /> Pelvic inflammatory disease develops in 10 to 20% of the females infected with ''N. gonorrhoeae''.<ref name="Sherris2" />

==== Neonates (perinatal infection) ====
In [[perinatal infection]], the primary manifestation is infection of the eye (neonatal conjunctivitis or [[Neonatal conjunctivitis|ophthalmia neonatorum]]) when the newborn is exposed to ''N. gonorrhoeae'' in the birth canal. The eye infection can lead to corneal scarring or perforation, ultimately resulting in blindness. If the newborn is exposed during birth, conjunctivitis occurs within 2–5 days after birth and is severe.<ref name="Sherris2" /><ref name="www.cdc.gov">{{Cite web|url=https://www.cdc.gov/std/tg2015/gonorrhea.htm|title=Gonococcal Infections - 2015 STD Treatment Guidelines|website=www.cdc.gov|language=en-us|access-date=2017-12-07}}</ref> Gonococcal ophthalmia neonatorum, once common in newborns, is prevented by the application of [[erythromycin]] (antibiotic) gel to the eyes of babies at birth as a public health measure. Silver nitrate is no longer used in the United States.<ref name="www.cdc.gov" /><ref name="Sherris2" />

===Transmission===
''N. gonorrhoeae'' is most often transmitted through vaginal, oral, or anal sex; nonsexual transmission is unlikely in adult infection.<ref name="www.cdc.gov_2017"/> It can also be transmitted to a newborn during passage through the birth canal if the mother has an untreated genitourinary infection. Given the high rate of asymptomatic infection, it is recommended that pregnant women be tested for gonococcal infection prior to birth.<ref name="www.cdc.gov_2017"/> Communal baths, shared towels or fabrics, rectal thermometers, and improper hand hygiene by caregivers have been identified as potential means of transmission in pediatric settings.<ref>{{cite journal | vauthors = Goodyear-Smith F | title = What is the evidence for non-sexual transmission of gonorrhoea in children after the neonatal period? A systematic review | journal = Journal of Forensic and Legal Medicine | volume = 14 | issue = 8 | pages = 489–502 | date = November 2007 | pmid = 17961874 | doi = 10.1016/j.jflm.2007.04.001 }}</ref>

Traditionally, the bacterium was thought to move attached to spermatozoa, but this hypothesis did not explain female to male transmission of the disease. A recent study suggests that rather than "surf" on wiggling [[sperm]], ''N. gonorrhoeae'' bacteria use pili to anchor onto proteins in the sperm and move through coital liquid.<ref name="Anderson2014">{{cite journal | vauthors = Anderson MT, Dewenter L, Maier B, Seifert HS | title = Seminal plasma initiates a Neisseria gonorrhoeae transmission state | journal = mBio | volume = 5 | issue = 2 | pages = e01004–e01013 | date = March 2014 | pmid = 24595372 | pmc = 3958800 | doi = 10.1128/mBio.01004-13 }}</ref>

=== Infection ===
Successful transmission is followed by adherence to the [[Epithelium|epithelial cells]] found at the infected mucosal site by the bacterium's [[Pilus|type IV pili]]. The pili's ability to attach and subsequently retract pulls ''N. gonorrhoeae'' towards the epithelial membrane at the surface of the mucosal cell.<ref name="Quillin_2018" /> Post attachment, ''N. gonorrhoeae'' replicates its genome and divides to form [[Microcolony|microcolonies]].<ref name="Quillin_2018" /> Gonococcal infection is sometimes aided by the membrane cofactor protein, CD46, as it has been known to act as a receptor for gonococcal pilus.<ref name="Edwards_2004" />  Additionally, interaction with pili has been shown to cause cytoskeletal rearrangement of the host cell, further demonstrating that gonococcal pili engagement disrupts the response of the host cell and increases the likelihood of successful infection.<ref name="Edwards_2004" /> During growth and colonization, ''N. gonorrhoeae'' stimulates the release of [[pro-inflammatory]] [[cytokine]]s and [[chemokine]]s from host immune cells that result in the recruitment of [[neutrophil]]s to the area.<ref name="Hill_2016" /> These [[Phagocyte|phagocytic cells]] typically take in foreign pathogens and destroy them, however, ''N. gonorrhoeae'''s ability to manipulate the host cell response allows the pathogen to survive within these immune cells and evade elimination.<ref name="Hill_2016" />

==== Laboratory diagnosis ====
The primary detection methods for ''Neisseria gonorrhoeae'' are [[Nucleic acid test|nucleic acid amplification tests]], which are the most sensitive techniques available.<ref name="Meyer_2020">{{cite journal | vauthors = Meyer T, Buder S | title = The Laboratory Diagnosis of ''Neisseria gonorrhoeae'': Current Testing and Future Demands | journal = Pathogens | volume = 9 | issue = 2 | pages = 91 | date = January 2020 | pmid = 32024032 | pmc = 7169389 | doi = 10.3390/pathogens9020091 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Cosentino LA, Campbell T, Jett A, Macio I, Zamborsky T, Cranston RD, Hillier SL | title = Use of nucleic acid amplification testing for diagnosis of anorectal sexually transmitted infections | journal = Journal of Clinical Microbiology | volume = 50 | issue = 6 | pages = 2005–2008 | date = June 2012 | pmid = 22493338 | pmc = 3372150 | doi = 10.1128/JCM.00185-12 }}</ref> Other methods of detection include microscopy and culture.<ref name="Meyer_2020" />

=== Prevention ===
Transmission is reduced by using latex barriers (e.g. [[condom]]s or [[dental dam]]s) during sex and by limiting sexual partners.<ref name="CDC">{{cite web | url = https://www.cdc.gov/std/tg2015/clinical.htm | archive-url = https://web.archive.org/web/20151222183741/https://www.cdc.gov/std/tg2015/clinical.htm | archive-date = 22 December 2015 | title = 2015 Sexually Transmitted Diseases Treatment Guidelines | work = CDC | publisher =  Centers for Disease Control and Prevention, U.S. Department of Health & Human Services}}</ref> Condoms and dental dams should be used during oral and anal sex as well. Spermicides, vaginal foams, and douches are not effective methods for transmission prevention.<ref name="Sherris" />

==== Vaccine ====
A vaccine against ''N. gonorrhoeae'' is becoming more necessary due to the growing incidence of cases, increasing [[antimicrobial resistance]], and its impact on reproductive health.<ref name="www.cdc.gov_2">{{Cite web |title=Gonococcal Infections Among Adolescents and Adults - STI Treatment Guidelines |url=https://www.cdc.gov/std/treatment-guidelines/gonorrhea-adults.htm |access-date=2024-11-19 |website=www.cdc.gov|date=5 December 2022 }}</ref> There are problems that have hampered vaccine development including: the absence of immunity post-infection, exclusively human hosts, and [[Antigenic variation|antigenic]] and [[phase variation]] of potential vaccine targets.<ref name="Williams_2024">{{cite journal | vauthors = Williams E, Seib KL, Fairley CK, Pollock GL, Hocking JS, McCarthy JS, Williamson DA | title = ''Neisseria gonorrhoeae'' vaccines: a contemporary overview | journal = Clinical Microbiology Reviews | volume = 37 | issue = 1 | pages = e0009423 | date = March 2024 | pmid = 38226640 | pmc = 10938898 | doi = 10.1128/cmr.00094-23 | veditors = Forrest GN }}</ref> Currently, there are several ''N. gonorrhoeae'' vaccines in development including an outer membrane vesicle vaccine.<ref name="Williams_2024" /> This includes the NGoXIM, the native OMV, and Bexsero/4CMenB vaccine candidates, which are all in the late clinical stages of development.<ref>{{ClinicalTrialsGov|NCT05630859|Safety and Efficacy of GSK Neisseria Gonorrhoeae GMMA (NgG) Investigational Vaccine When Administered to Healthy Adults 18 to 50 Years of Age.}}</ref> The creation of a vaccine for ''N. gonorrhoeae'' has several potential public health impacts. In one estimate, a vaccine for the heterosexual population given before sexual activity occurs showed that prevalence of ''N. gonorrhoeae'' could be reduced by up to 90% after 20 years.<ref name="Williams_2024" />

===Treatment===
Currently, the [[Centers for Disease Control and Prevention|CDC]] recommends a single dose of the injectable [[cephalosporin]], [[ceftriaxone]], as the first line of defense against gonococcal infections.<ref>{{Cite web |last=CDC |date=2024-05-16 |title=Drug-Resistant Gonorrhea |url=https://www.cdc.gov/gonorrhea/hcp/drug-resistant/index.html#:~:text=Currently,%20just%20one%20regimen%20is,to%20cephalosporins%20and%20other%20drugs. |access-date=2024-11-20 |website=Gonorrhea |language=en-us}}</ref> Individuals weighing less than 150&nbsp;kg are typically prescribed a ceftriaxone concentration of 500&nbsp;mg, while individuals who weigh over 150&nbsp;kg are typically prescribed a dose of 1 g. Although ceftriaxone is not the only cephalosporin that has been effective at treating gonorrhoeae, it is the most advantageous.<ref name="www.cdc.gov_2" /> In the event of a cephalosporin allergy, the CDC recommends a dual treatment of [[gentamicin]] and [[azithromycin]]. Each drug should be administered as a single dose, with the gentamicin entering intramuscularly at a concentration of 240&nbsp;mg, along with 2 g of azithromycin taken orally.<ref name="www.cdc.gov_2" /> If an individual is not allergic to cephalosporins but ceftriaxone is unavailable, an alternative treatment is a single dose of 800&nbsp;mg cefixime consumed orally.<ref name="www.cdc.gov_2" /> In all of these cases, combination therapy and co-treatment for chlamydia is recommended, as simultaneous infections are common.<ref>{{cite journal | vauthors = St Cyr S, Barbee L, Workowski KA, Bachmann LH, Pham C, Schlanger K, Torrone E, Weinstock H, Kersh EN, Thorpe P | title = Update to CDC's Treatment Guidelines for Gonococcal Infection, 2020 | language = en-us | journal = MMWR. Morbidity and Mortality Weekly Report | volume = 69 | issue = 50 | pages = 1911–1916 | date = December 2020 | pmid = 33332296 | doi = 10.15585/mmwr.mm6950a6 | pmc = 7745960 }}</ref> 
 
==== Antibiotic resistance ====
[[Antibiotic resistance in gonorrhea]] was first identified in the 1940s. Gonorrhea was treated with penicillin, but doses had to be progressively increased to remain effective. By the 1970s, penicillin-and tetracycline-resistant gonorrhea emerged in the Pacific Basin. These resistant strains then spread to Hawaii, California, the rest of the United States, Australia and Europe. Fluoroquinolones were the next line of defense, but soon resistance to this antibiotic emerged, as well. Since 2007, standard treatment has been third-generation cephalosporins, such as ceftriaxone, which are considered to be our "last line of defense".<ref>{{cite news|url=https://www.bbc.co.uk/news/health-15238613|title=UK doctors advised gonorrhoea has turned drug resistant|date=10 October 2011|work=BBC News}}</ref><ref name="blog.advocatesaz.org">{{cite web | url = http://blog.advocatesaz.org/2012/03/06/sti-awareness-antibiotic-resistant-gonorrhea | archive-url = https://web.archive.org/web/20121105124828/http://blog.advocatesaz.org/2012/03/06/sti-awareness-antibiotic-resistant-gonorrhea/ | archive-date = 5 November 2012 | title = STI Awareness: Antibiotic-Resistant Gonorrhea | publisher = Planned Parenthood Advocates of Arizona | date = 6 March 2012 | access-date = 6 March 2012 }}</ref> Recently, a high-level ceftriaxone-resistant strain of gonorrhea called H041 was discovered in Japan. Lab tests found it to be resistant to high concentrations of ceftriaxone, as well as most of the other antibiotics tested. Within ''N. gonorrhoeae'', genes exist that confer resistance to every single antibiotic used to cure gonorrhea, but thus far they do not coexist within a single gonococcus. However, because of ''N. gonorrhoeae''{{'}}s high affinity for horizontal gene transfer, antibiotic-resistant gonorrhea is seen as an emerging public health threat.<ref name="blog.advocatesaz.org" />

Prior to 2007, [[fluoroquinolone]]s were a common treatment recommendation for gonorrhoeae. The CDC stopped suggesting these systemic bacterial agents once a resistant strain of ''N. gonorrhoeae'' emerged in the United States. The removal of fluoroquinolones as a potential treatment left [[cephalosporin]]s as the only viable antimicrobial option for gonorrhea treatment. Wary of further gonococcal resistance, the CDC's recommendations shifted in 2010 to a dual therapy strategy—cephalosporin with either [[azithromycin]] or [[doxycycline]]. Despite these efforts, resistant ''N. gonorrhoeae'' had been reported in five continents by 2011, further limiting treatment options and recommendations. Antimicrobial resistance is not universal and ''N. gonorrhoeae'' strains in the United States continue to respond to a combination regimen of [[ceftriaxone]] and azithromycin.<ref name="pmid35015033">{{cite journal |vauthors=Tuddenham S, Hamill MM, Ghanem KG |title=Diagnosis and Treatment of Sexually Transmitted Infections: A Review |journal=JAMA |volume=327 |issue=2 |pages=161–172 |date=January 2022 |pmid=35015033 |doi=10.1001/jama.2021.23487 |url=}}</ref>

=== Serum resistance ===
As a Gram negative bacterium, ''N. gonorrhoeae'' requires defense mechanisms to protect itself against the [[complement system]] (or complement cascade), whose components are found with human [[Serum (blood)|serum]].<ref name="Edwards_2004"/> There are three different pathways that activate this system however, they all result in the activation of complement protein 3 (C3).<ref name="Janeway Jr_2001">{{cite book |last1=Charles A Janeway |first1=Jr |last2=Travers |first2=Paul |last3=Walport |first3=Mark |last4=Shlomchik |first4=Mark J. |title=Immunobiology: The Immune System in Health and Disease. 5th edition |date=2001 |publisher=Garland Science |chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK27100/ |chapter=The complement system and innate immunity }}</ref> A cleaved portion of this protein, [[C3b]], is deposited on pathogenic surfaces and results in [[Opsonin|opsonization]] as well as the downstream activation of the [[Complement membrane attack complex|membrane attack complex]].<ref name="Janeway Jr_2001"/> ''N. gonorrhoeae'' has several mechanisms to avoid this action.<ref name="Quillin_2018"/> As a whole, these mechanisms are referred to as serum resistance.<ref name="Quillin_2018"/>