Two of the drug's three components were originally developed at the Public Health Agency of Canada's National Microbiology Laboratory (NML), and a third at the U.S. Army Medical Research Institute of Infectious Diseases; [ 2 ]  the cocktail was optimized by Gary Kobinger, then branch chief of the NML, and is undergoing further development by Leaf Biopharmaceutical (LeafBio, Inc.), a San Diego–based arm of Mapp Biopharmaceutical. [ 12 ]  LeafBio created ZMapp in collaboration with its parent and Defyrus Inc., each of which had licensed its own cocktail of antibodies, called MB-003 and ZMab. [ 13 ] [ citation needed ]


MB-003 is a cocktail of three humanized or human–mouse chimeric mAbs: c13C6, h13F6, and c6D8. [ 7 ]  A study published in September 2012 found that  rhesus macaques  infected with  Ebola virus  (EBOV) survived when receiving MB-003 (mixture of 3 chimeric monoclonal antibodies) one hour after infection. When treated 24 or 48 hours after infection, four of six animals survived and had little to no  viremia  and few, if any, clinical symptoms. [ 14 ]


MB-003 was created by scientists at the U.S. Army Medical Research Institute of Infectious Diseases, Gene Olinger, and Jamie Pettitt in collaboration with Mapp Biopharmaceutical with years of funding from US government agencies including the  National Institute of Allergy and Infectious Disease ,  Biomedical Advanced Research and Development Authority , and the  Defense Threat Reduction Agency . [ 1 ] [ 2 ] [ 15 ]


ZMAb is a mixture of three mouse mAbs: m1H3, m2G4, and m4G7. [ 7 ]  A study published in November 2013 found that EBOV-infected  macaque  monkeys survived after being given a therapy with a combination of three EBOV surface  glycoprotein  (EBOV-GP)-specific monoclonal antibodies (ZMAb) within 24 hours of infection. The authors concluded that post-exposure treatment resulted in a robust immune response, with good protection for up to 10 weeks and some protection at 13 weeks. [ 16 ]  ZMab was created by the NML and licensed to Defyrus, a Toronto-based  biodefense  company, with further funding by the  Public Health Agency of Canada . [ 2 ]


A 2014 paper described how Mapp and its collaborators, including investigators at  Public Health Agency of Canada , Kentucky BioProcessing, and the  National Institute of Allergy and Infectious Diseases , first  chimerized  the three antibodies comprising ZMAb, then tested combinations of MB-003 and the chimeric ZMAb antibodies in guinea pigs and then primates to determine the best combination, which turned out to be c13C6 from MB-003 and two chimeric mAbs from ZMAb, c2G4 and c4G7. This is ZMapp. [ 7 ]


In an experiment also published in the 2014 paper, 21  rhesus macaque  primates were infected with the  Kikwit  Congolese variant of EBOV. Three primates in the control arm were given a non-functional antibody, and the 18 in the treatment arm were divided into three groups of six. All primates in the treatment arm received three doses of ZMapp, spaced 3 days apart. The first treatment group received its first dose on 3rd day after being infected; the second group on the 4th day after being infected, and the third group, on the 5th day after being infected. All three primates in the control group died; all 18 primates in the treatment arm survived. [ 7 ]  Mapp then went on to show that ZMapp inhibits replication of a Guinean strain of EBOV in cell cultures. [ 17 ]


Mapp remains involved in the production of the drug through its contracts with Kentucky BioProcessing, a subsidiary of  Reynolds American . [ 1 ]  To produce the drug, genes coding for the chimeric mAbs were inserted into  viral vectors , and tobacco plants are infected with the viral vector encoding for the antibodies, using  Agrobacterium  cultures. [ 18 ] [ 19 ] [ 20 ]  Subsequently, antibodies are extracted and purified from the plants. Once the genes encoding the chimeric mAbs are in hand, the entire tobacco production cycle is believed to take a few months. [ 3 ]  The development of these production methods was funded by the U.S.  Defense Advanced Research Projects Agency  as part of its bio-defense efforts following the 9/11 terrorist attacks. [ 21 ] [ 22 ]


ZMapp was first used during the 2014 West Africa Ebola Virus outbreak, having not previously undergone any human clinical trials to determine its efficacy or potential risks. [ 3 ]  By October 2014, the  United States Food and Drug Administration  had approved the use of several experimental drugs, including ZMapp, to be used on patients infected with Ebola virus. The use of such drugs during the epidemic was also deemed ethical by the  World Health Organization  (WHO). [ 23 ]  In 2014, a limited supply of ZMapp was used to treat 7 individuals infected with the Ebola virus; of these 2 died. [ 24 ] [ 25 ]  The outcome is not considered to be  statistically significant . Mapp announced in August 2014, that supplies of ZMapp had been exhausted. [ 26 ]


The lack of drugs and unavailability of experimental treatment in the most affected regions of the West African Ebola virus outbreak spurred some controversy. [ 3 ]  The fact that the drug was first given to Americans and a European and not to Africans, according to the  Los Angeles Times , "provoked outrage, feeding into African perceptions of Western insensitivity and arrogance, with a deep sense of mistrust and betrayal still lingering over the exploitation and abuses of the colonial era". [ 27 ]   Salim S. Abdool Karim , the director of an AIDS research center in South Africa, placed the issue in the context of the history of exploitation and abuses. Responding to a question on how people might have reacted if ZMapp and other drugs had first been used on Africans, he said "It would have been the front-page screaming headline: 'Africans used as guinea pigs for American drug company's medicine ' ". [ 3 ]


In August 2014, the World Health Organization called for convening a panel of medical authorities "to consider whether experimental drugs should be more widely released." In a statement,  Peter Piot  (co-discoverer of the Ebola virus); Jeremy Farrar, the director of the  Wellcome Trust ; and David Heymann of the Chatham House Center on Global Health Security, called for the release of experimental drugs for the  2014 West Africa Ebola outbreak . [ 27 ]


At an August 2014 press conference,  Barack Obama , the  President of the United States , was questioned regarding whether the cocktail should be fast-tracked for approval or be made available to sick patients outside of the United States. He responded, "I think we've got to let the science guide us. I don't think all the information's in on whether this drug is helpful." [ 28 ]


The  National Institutes of Health  announced on 27 February 2015 the commencement of a randomized controlled trial of ZMapp to be conducted in Liberia and the United States. [ 29 ]  From March 2015 through November 2015, 72 individuals infected with the Ebola virus were enrolled in the trial; investigators stopped enrolling new subjects in January 2016, having failed to reach its enrollment goal of 200 due to the waning of the  Ebola outbreak . As a result, although a 40% lower risk of death was calculated for those who received ZMapp, the difference was not statistically significant and ultimately it could not be determined whether the use of ZMapp was superior to the optimized standard of care alone. However, ZMapp was found to be safe and well tolerated. [ 4 ] [ 30 ] [ 31 ]


The ZMapp cocktail was assessed by the World Health Organization for emergency use under the  Monitored Emergency Use of Unregistered and Investigational Interventions  (MEURI) ethical protocol. The panel agreed that "the benefits of ZMapp outweigh its risks" while noting that it presented logistical challenges, particularly that of requiring a  cold chain  for distribution and storage. [ 32 ]  Four alternative therapies ( remdesivir , the  Regeneron  product  atoltivimab/maftivimab/odesivimab ,  favipiravir , and  ansuvimab ) were also considered for use, but they were at earlier stages of development. [ 32 ]
In August 2019, the Democratic Republic of the Congo's national health authorities, the World Health Organization, and the National Institutes of Health announced that they would stop using ZMapp, along with all other Ebola treatments except atoltivimab/maftivimab/odesivimab and ansuvimab, in their ongoing clinical trials, citing the higher mortality rates of patients not treated with atoltivimab/maftivimab/odesivimab and ansuvimab. [ 33 ] [ 34 ]


In October 2020, the US  Food and Drug Administration  (FDA) approved atoltivimab/maftivimab/odesivimab with an  indication  for the treatment of infection caused by  Zaire ebolavirus . [ 35 ]


map of DRC (Democratic Republic of the Congo)


28 January 2019


NordNordWest, DaB.


See below.


Neisseria gonorrhoeae , the bacterium that causes the sexually transmitted infection  gonorrhea , has developed  antibiotic resistance  to many antibiotics. The bacteria was first identified in 1879. [ 1 ]


In the 1940s effective treatment with  penicillin  became available, but by the 1970s resistant strains predominated. Resistance to penicillin has developed through two mechanisms: chromosomally mediated resistance (CMRNG) and penicillinase-mediated resistance (PPNG). CMRNG involves step wise mutation of penA, which codes for the  penicillin-binding protein  (PBP-2); mtr, which encodes an  efflux pump  that removes penicillin from the cell; and penB, which encodes the bacterial cell wall  porins . PPNG involves the acquisition of a  plasmid-borne   beta-lactamase . [ 2 ]   N. gonorrhoeae  has a high affinity for  horizontal gene transfer , and as a result, the existence of any strain resistant to a given drug could spread easily across strains. [ citation needed ]


Fluoroquinolones  were a useful next-line treatment until resistance was achieved through efflux pumps and mutations to the gyrA gene, which encodes  DNA gyrase . [ 2 ]  Third-generation  cephalosporins  have been used to treat gonorrhoea since 2007, but resistant strains have emerged. As of 2010, the recommended treatment is a single 250 mg intramuscular injection of  ceftriaxone , sometimes in combination with  azithromycin  or  doxycycline . [ 3 ] [ 4 ]  However, certain strains of  N. gonorrhoeae  can be resistant to antibiotics that are normally used to treat it. These include:  cefixime  (an oral  cephalosporin ),  ceftriaxone  (an injectable cephalosporin),  azithromycin ,  aminoglycosides , and  tetracycline . [ 5 ] [ 6 ]


Beta-lactams like penicillin were widely used to treat  gonorrhea  in the 1940s.  There are three general mechanisms that may allow bacteria to become resistant to beta-lactam antibiotics:


Overuse of penicillin contributed to  Neisseria gonorrhoeae  developing high resistance to penicillin through two main mechanisms: chromosomally mediated resistance (CMRNG) and penicillinase-mediated resistance (PPNG). [ 2 ]


Chromosomally mediated resistance occurred through step-wise changes over many years.  Chromosomal mutations in the  penA ,  mtr , and  penB  genes are the major mechanisms for CMRNG.  The  penA  gene encodes an alternative penicillin-binding protein, PBP-2. [ 2 ]   This mechanism falls under the second general mechanism for beta-lactam resistance.  PBPs, also known as transpeptidases, are targets for beta-lactams.  These enzymes (PBPs) are involved in peptidoglycan synthesis which is a major component of the bacterial cell wall.  PBPs cross-link the amino acid strands of peptidoglycan during synthesis.  Normally, beta-lactams bind the PBPs and thereby inhibit the cross-linking of peptidoglycan.  When this occurs, the cell wall of the bacterium is compromised and often results in cell death. [ 7 ]   When  N. gonorrhoeae  encodes  penA , the new PBP-2 that is synthesized is no longer recognized by the beta-lactams rendering the bacterium resistant. [ citation needed ]


The  mtr  (multiple transferable resistance) gene encodes for an efflux pump. [ 8 ]   Efflux pumps mediate resistance to a variety of compounds including antibiotics, detergents, and dyes. [ 2 ]   This mechanism falls under the first general resistance mechanism to beta-lactams.   mtr  encodes for the protein MtrD which is the efflux pump for  N. gonorrhoeae . [ 2 ]   MtrD is among the Resistance Nodulation Division (RND) efflux pump superfamily.  These pumps are proton antiporters where the antibiotic is pumped out of the cell while a proton is pumped into the cell. [ 9 ]


The cell wall of  N. gonorrhoeae  contains porins which are holes within the cell wall in which some molecules are able to diffuse into or out of the cell membrane.  This mechanism falls under the first general mechanism for beta-lactam resistance.  The  penB  gene encodes the porins for  N. gonorrhoeae  and when this gene undergoes mutations, there is a decrease in permeability of the cell wall to hydrophilic antibiotics like penicillin. [ 2 ]


Penicillinase-mediated resistance in  N. gonorrhoeae  is mediated by the plasmid borne TEM-1 type beta-lactamase which falls under the third general mechanism for beta-lactam resistance. [ 2 ]   There have been over 200 beta-lactamases described and some of them are antibiotic specific. [ 7 ]   TEM-1 is a penicillinase specific for penicillins.  This enzyme will bind to the beta-lactam ring which is a structural characteristic for beta-lactams and hydrolyze the ring.  This renders the antibiotic inactive.  The spread of the penicillinase resistance was much faster compared to the chromosomal-mediated resistance mechanisms.  The plasmids containing TEM-1 could be passed from bacterium to bacterium via conjugation  [ 2 ]


Quinolones are a class of synthetic antibiotics that inhibit DNA replication, recombination, and repair by interacting with the bacterial DNA gyrase and/or topoisomerase IV. [ 7 ]   Second generation quinolones like ciprofloxacin and ofloxacin have been widely used to treat  N. gonorrhoeae  infections.  Resistance to these antibiotics has developed over the years with chromosomal resistance being the primary mechanism. [ 2 ]


Low-level quinolone resistance has been linked to changes in cell permeability and efflux pumps.  The NorM efflux pump is encoded by the  norM  gene and provides resistance to fluoroquinolones. [ 8 ]   The NorM efflux pump is a member of the MATE (multidrug and toxic compound extrusion) family and functions by a Na+ antiporter.  It is also known that a point mutation upstream of the  norM  gene will causes overexpression of NorM, and mediate elevated resistance. [ 8 ]


High-level resistance to quinolones has been seen through target modification acting on the DNA gyrase and topoisomerase IV.  Multiple amino acid substation mutations in the  gyrA  gene, which encodes for the DNA gyrase, have been seen extensively.  DNA gyrase is an enzyme that binds to DNA and introduces negative supercoiling. [ 10 ]   This helps unwind the DNA for replication.  If there is a mutation in the DNA gyrase, then the quinolone will not be able to bind to it resulting in the activity of DNA gyrase not being inhibited.  Multiple mutations have also been noted in the  parC  gene which encodes for the topoisomerase IV.  Topoisomerase IV acts similarly to DNA gyrase and is involved in unwinding DNA for replication. [ 10 ]


Ceftriaxone  and  cefixime  are third generation cephalosporins and are often used as treatments for  N. gonorrhoeae infections . [ 2 ]   The cephalosporins are part of a larger beta-lactam family of antibiotics. [ 11 ]   The newly discovered H041 strain of  N. gonorrhoeae , originally isolated from a commercial sex worker in Japan, was shown to be resistant to this antibiotic. [ 12 ]


The possible mechanisms of resistance to this antibiotic are as follows:


Tetracyclines are a class of antibiotics that inhibit protein synthesis by binding to the 30s ribosomal subunit of bacterial cells, keeping transcription of the bacterial genome from occurring. [ 11 ]   Tetracyclines are bacteriostatic, which means that the growth of the bacterium will be slowed. [ 7 ]   Tetracyclines are not often recommended for the treatment of  N. gonorrhoeae  because the treatment regimen requires many doses, which may affect compliance and contribute to resistance. [ 2 ]   Tetracycline is still used as treatment for this infection in developing countries because the cost for the drug is low  [ 2 ]


As with the penicillin resistance, the  penB  (porin formation) and  mtr  (efflux pump formation) mutations mediate chromosomal resistance.  These adaptations will also affect the ability of the antibiotic to get into, or stay in the bacterial cell.  High level resistance of  N. gonorrhoeae  to tetracyclines was first reported in 1986 with the discovering of the  tetM  determinant. [ 2 ]   The mechanism of resistance is still unknown.


N. gonorrhoeae  has also shown resistance to the  aminoglycoside  class of antibiotics. These antibiotics bind to the 16s rRNA of the 30S subunit of the bacterial ribosome, [ 11 ]  thereby inhibiting mRNA translation and protein synthesis.  Resistance appears to be acquired through porin-related mechanisms, much like the cephalosporin resistance mechanism.  This mechanism would result in the access of the antibiotic to the bacterial cell being inhibited.  There is a possibility of future enzymes (made by the bacterium) that will be able to denature and inactivate the aminoglycosides. [ 2 ]


Blennorrhea  is  mucous  discharge, especially from the  urethra  or  vagina  (that is, mucus  vaginal discharge ). [ 1 ] Blennorrhagia  is an excess of such discharge, [ 2 ]  often specifically referring to that seen in  gonorrhea .


This article about a disease of the genitourinary system is a  stub . You can help Wikipedia by  expanding it .


This  women's health  related article is a  stub . You can help Wikipedia by  expanding it .


Gonorrhoea  is a  sexually transmitted infection  (STI) caused by the bacterium  Neisseria gonorrhoeae . [ 1 ]


The  World Health Organization  (WHO) estimated that, in 2016, the global  incidence rate  was 20 per 1000 women and 26 per 1000 men, totaling 86.9 million new gonococcal infections among people between 15 and 49 years old. [ 2 ]


As of 2018, gonorrhoea was the second most commonly reported STI in  Canada . Its incidence rate has been rising since 1997.


Incidence rate among men was consistently higher than that among women (70.2 per 100,000 versus 40.6 per 100,000 in 2015). It was also increasing faster among men than women (85.2% versus 39.5% in 2010–2015). People between 15 and 29 years old had the highest rate. Geographically, the highest gonorrhoea rates in 2015 were found in the  Northwest Territories ,  Nunavut  and  Yukon . [ 3 ]


In  Nordic countries , gonorrhoea affects mainly young people below the age of 30. Infections are more common in men than in women. Nearly half of the reported cases of gonorrhoea are attributed to  men who have sex with men  (MSM). [ 4 ]


Greenlandic women have the highest incidence rate. In contrast to the other Nordic countries, in  Greenland , the numbers of cases among women and among men are almost equally high. Incidence rates are significantly lower in the other Nordic countries. However, cases are rising in  Denmark ,  Iceland ,  Norway  and  Sweden . The  Faroe Islands  has relatively few cases. [ 4 ]


In  England , there were 82,592 diagnoses of gonorrhoea in 2022, an increase of 50.3% compared to 2021 (54,961). The number of gonorrhoea diagnoses in 2022 was the largest annual number reported since records began. [ 5 ]


Diagnoses were increasing in people of all ages in England, but the rise was highest among young people aged 15 to 24 years. [ 5 ]  This trend was also detected in Scotland. [ 6 ]


Sexually transmitted disease surveillance 2020  published by the  Centers for Disease Control and Prevention  (CDC) showed that, in 2020, a total of 677,769 cases of gonorrhea were reported to the CDC, a 45 percent increase from 2016, [ 7 ] making it the second most common notifiable sexually transmitted infection in the United States for that year. Rates of reported gonorrhea have increased 111% since the historic low in 2009. During 2019–2020, the overall rate of reported gonorrhea increased 5.7%; rates increased among both males and females and in three regions of the United States (Midwest, Northeast, and South); rates of reported gonorrhea increased in 36 states and two US territories. [ 8 ]


Since 2013, rates have been higher among men compared to women, likely reflecting cases identified in both men who have sex with men (MSM) and men who have sex with women only. Although there are limited data available on sexual behaviors of persons reported with gonorrhea at the national level, enhanced data from jurisdictions participating in a sentinel surveillance system, the STD Surveillance Network (SSuN), suggest that about a third of gonorrhea cases occurred among MSM in 2020. During 2019–2020, rates increased among both men and women, but increases were greater among women (15%) compared to men (6.6%) which may reflect differences in diagnosing and reporting of cases among MSM in 2020. As extragenital infections are often asymptomatic and are likely identified by screening, diagnoses among MSM may have been reduced in 2020 due to the effect of the  COVID-19 pandemic  on screening coverage. [ 8 ]


Gonorrhoea can quickly develop resistance to  antibiotics  used to treat infection, and in 2020, about half of all infections were estimated to be resistant to at least one antibiotic. Since 2010, almost all circulating strains in the United States, based on gonococcal isolates collected through sentinel surveillance in the Gonococcal Isolate Surveillance Project (GISP), remain susceptible to  ceftriaxone , the primary treatment for gonorrhea; only 0.1% of isolates displayed elevated ceftriaxone minimum inhibitory concentrations (MICs) in 2020. In 2020, 5.8% of isolates had elevated  azithromycin  MICs; the proportion was higher among MSM compared to men who have sex with women only (9.2% vs 4.3%). [ 8 ]


Fitz-Hugh–Curtis syndrome  is a rare complication of  pelvic inflammatory disease  (PID) involving  liver capsule   inflammation [ 1 ]  leading to the formation of  adhesions  presenting with the clinical syndrome of right upper quadrant (RUQ) pain.


Fitz-Hugh–Curtis syndrome, or perihepatitis, was first described by Carlos Stajano in 1920, who found adhesions between the liver capsule and the abdominal wall in patients suffering from gonococcal infections. [ 2 ]


The condition is named after the two physicians, Thomas Fitz-Hugh Jr. and  Arthur Hale Curtis , who further studied the syndrome in the 1930s. They noted the classic "violin string adhesions" in female patients presenting with RUQ  abdominal pain . Both Fitz-Hugh and Curtis regularly found these adhesions during laparotomy in patients with the clinical syndrome of RUQ with concern for gallbladder pathology; however, no abdominal pathology was found in these patients but residual gonococcal tubal changes were often noted. [ 3 ] [ 4 ]


Fitz-Hugh–Curtis syndrome occurs almost exclusively in women, though it can be seen in males rarely. [ 5 ]  It is complication of  pelvic inflammatory disease  (PID) caused by  Chlamydia trachomatis  (Chlamydia) or  Neisseria gonorrhoeae  (Gonorrhea) though other bacteria such as  Bacteroides ,  Gardnerella ,  E. coli  and  Streptococcus  have also been found to cause Fitz-Hugh–Curtis syndrome on occasion. [ 6 ]  Fitz-Hugh–Curtis syndrome was originally studied solely as a complication of PID secondary to Gonorrhea, but studies have now shown that Chlamydia is the most common causal pathogen. [ 7 ]  Fitz-Hugh–Curtis syndrome occurs in 5-15% of patients with PID. [ 8 ]


The pathogens of PID spread either spontaneous secondary to an ascending infection through the  fallopian tubes , lymphatically, or hematogenous. [ 9 ] [ 10 ] [ 11 ]  Inflammation then causes scar tissue to form on  Glisson's capsule , a thin layer of connective tissue surrounding the liver. [ 12 ]  This inflammation and scaring then leads to the characteristic RUQ pain.


The major symptom and signs include an acute onset of RUQ  abdominal pain  aggravated by breathing, coughing or laughing, which may also present with  referred pain  to the right shoulder.  There is usually also tenderness on palpation of the right upper abdomen and tenderness to percussion of the lower ribs which protect the liver. Patients may also report fevers, malaise, back pain, pelvic pain,  dyspareunia , vaginal discharge, and  dysuria . [ 13 ] [ 14 ]


Patients are most often women of childbearing age. There are a number of risk factors for the development of Fitz-Hugh–Curtis syndrome, these include having multiple sexual partners, history of sexually transmitted disease, history of PID, use of an  intrauterine device , use of a vaginal  douche , and being under the age of 25.


The signs and symptoms of Fitz-Hugh–Curtis syndrome greatly overlap with numerous other abdominal and pelvic pathologies. It is important for practitioners to perform a thorough history and physical as the differential for the symptoms of Fitz-Hugh–Curtis syndrome include cholecystitis, appendicitis, hepatitis, pregnancy, pyelonephritis, renal colic, pleuritic causes such as pneumonia, pulmonary embolism, and pleurisy, among many others. [ 15 ]


The workup for Fitz-Hugh–Curtis syndrome at presentation begins with ruling out pregnancy or an ectopic pregnancy with a pregnancy test, this can also help guide antibiotic therapy if indicated to prevent teratogens.


Radiographic studies are often indicated to rule out other thoracic, abdominal, and pelvic pathologies. Chest and abdominal radiographs may be indicated to rule out pulmonary pathologies and to assess for free air under the diaphragm in the case of intestinal perforation. Abdominal and pelvic ultrasounds are critical to rule out common causes of RUQ pain such as cholelithiasis, cholecystitis, and abdominal/pelvic abscesses.  Computed tomography  (CT) scan should be obtained in the case that the clinical suspicion for appendicitis is high. In cases of Fitz-Hugh–Curtis syndrome, the CT scan may show increased blood flow to the liver capsule secondary to the inflammation.


Liver function tests (LFTs)  are often obtained is these patients as part of the initial workup, since Fitz-Hugh–Curtis syndrome does not involve direct damage to the liver, LFTs will be normal or only slightly elevated. [ 16 ]


After ruling out other concerning pathologies if suspicion is high, the workup for Fitz-Hugh–Curtis syndrome involves testing for sexually transmitted diseases (Chlamydia and Gonorrhea) with  nucleic acid amplification tests (NAATs)  from a cervical swab sample. If indicated, urethral, rectal, and/or pharyngeal swabs may be obtained as well.


The gold standard for diagnosis of Fitz-Hugh–Curtis syndrome, though rarely required, is  laparoscopy  with direct visualization of the characteristic "violin string adhesions" along with liver capsule scarring and inflammation. Antibody testing of 57-kDa chlamydial heat-shock protein can be done in cases where all other tests have been non-diagnostic and the clinical suspicion remains high. [ 17 ]


The mainstay of treatment of Fitz-Hugh–Curtis syndrome is antibiotics targeted at the causal organism. The CDC recommends a low threshold for treatment given the high risk of infertility and ectopic pregnancies with untreated disease. [ 18 ]  Antibiotic therapy should cover the most common pathogens including Chlamydia, Gonorrhea, other gram-negatives, and anaerobes. [ 19 ]  Current guidelines recommend  ceftriaxone  and  azithromycin  as Chlamydia and Gonorrhea constitute the vast majority of cases, treatment for complicated PID involves the combination of ceftriaxone,  doxycycline , and  metronidazole . [ 20 ] [ 21 ]  In cases of refractory pain, laparoscopy may be considered for lysis of adhesions.


With treatment, the prognosis of Fitz-Hugh–Curtis syndrome is excellent with vast majority of patients seeing complete resolution of symptoms. Complications of the disease include infertility, small bowel obstruction due to adhesions, chronic pelvic pain, recurrent salpingitis, and ectopic pregnancy. [ 22 ] [ 23 ] [ 24 ]


Gonorrhoea  or  gonorrhea , colloquially known as  the clap , [ 7 ]  is a  sexually transmitted infection  (STI) caused by the bacterium  Neisseria gonorrhoeae . [ 8 ]  Infection may involve the  genitals , mouth, or  rectum . [ 9 ]


Gonorrhea is spread through sexual contact with an infected person, [ 1 ]  or from a  mother to a child during birth . [ 1 ]   Infected males may experience  pain or burning with urination , discharge from the  penis , or  testicular pain . [ 1 ]  Infected females may experience burning with urination,  vaginal discharge , vaginal bleeding between  periods , or  pelvic pain . [ 1 ]  Complications in females include  pelvic inflammatory disease  and in males include  inflammation of the epididymis . [ 1 ]  Many of those infected, however, have no symptoms. [ 1 ]  If untreated, gonorrhea can spread to  joints  or  heart valves . [ 1 ] [ 2 ]  Gonorrhea affects about 0.8% of women and 0.6% of men. [ 6 ]  An estimated 33 to 106 million new cases occur each year. [ 10 ] [ 11 ]  In 2015, it caused about 700 deaths. [ 12 ]


Diagnosis is by testing the urine,  urethra  in males,  vagina  or  cervix  in females. It can be diagnosed by testing a sample collected from the throat or rectum of individuals who have had oral or anal sex, respectively. [ 1 ]  Testing all women who are sexually active and less than 25 years of age each year as well as those with new sexual partners is recommended; [ 3 ]  the same recommendation applies in  men who have sex with men  (MSM). [ 3 ]
Gonorrhea can be prevented with the use of  condoms , having sex with only one person who is uninfected, and by  not having sex . [ 1 ] [ 3 ]  Treatment is usually with  ceftriaxone  by injection and  azithromycin  by mouth. [ 4 ] [ 5 ]   Resistance  has developed to many previously used  antibiotics  and higher doses of ceftriaxone are occasionally required. [ 4 ] [ 5 ]


Gonorrhea infections of  mucosal membranes  can cause swelling, itching, pain, and the formation of  pus . [ 13 ]  The  time from exposure to symptoms  is usually between two and 14 days, with most symptoms appearing between four and six days after infection, if they appear at all.  Both men and women with infections of the throat may experience a  sore throat , though such infection does not produce symptoms in 90% of cases. [ 14 ] [ 15 ]  Other symptoms may include swollen lymph nodes around the neck. [ 13 ]  Either sex can become infected in the eyes or rectum if these tissues are exposed to the bacterium, [ 16 ]  which can lead to pain with bowel movements, rectal discharge, or constipation. [ 17 ]


Half of women with gonorrhea are  asymptomatic  but the other half experience  vaginal discharge , lower abdominal pain, or  pain with sexual intercourse  associated with  inflammation of the uterine cervix . [ 18 ] [ 19 ] [ 20 ]  Common medical complications of untreated gonorrhea in women include  pelvic inflammatory disease  which can cause scars to the  fallopian tubes  and result in later  ectopic pregnancy  among those women who become pregnant. [ 21 ]


Most infected men with symptoms have  inflammation of the penile urethra  associated with a  burning sensation during urination  and discharge from the penis. [ 19 ]  In men, discharge with or without burning occurs in half of all cases and is the most common symptom of the infection. [ 22 ]  This pain is caused by a narrowing and stiffening of the urethral  lumen . [ 23 ]  The most common medical complication of gonorrhea in men is  inflammation of the epididymis . [ 21 ]  Gonorrhea is also associated with increased risk of  prostate cancer . [ 24 ]


If not treated,  gonococcal ophthalmia neonatorum  will develop in 28% of infants born to women with gonorrhea. [ 25 ]


If left untreated, gonorrhea can spread from the original site of infection and infect and damage the joints, skin, and other organs. Indications of this can include fever, skin rashes, sores, and joint pain and swelling. [ 21 ]  In advanced cases, gonorrhea may cause a general  feeling of tiredness  similar to other infections. [ 26 ] [ 22 ]  It is also possible for an individual to have an  allergic reaction  to the bacteria, in which case any appearing symptoms will be greatly intensified. [ 22 ]  Very rarely it may settle in the heart, causing  endocarditis , or in the spinal column, causing  meningitis . Both are more likely among individuals with suppressed immune systems, however. [ 15 ]


Gonorrhea is caused by the bacterium  Neisseria gonorrhoeae . [ 19 ]  Previous infection does not confer immunity – a person who has been infected can become infected again by exposure to someone who is infected. Infected persons may be able to infect others repeatedly without having any signs or symptoms of their own. [ 27 ]


The infection is usually spread from one person to another through  vaginal ,  oral , or  anal sex . [ 19 ] [ 28 ]  Men have a 20% risk of getting the infection from a single act of vaginal intercourse with an infected woman. The risk for  men who have sex with men  (MSM) is higher. [ 29 ]  Insertive MSM may get a penile infection from anal intercourse, while receptive MSM may get anorectal gonorrhea. Women have a 60–80% risk of getting the infection from a single act of vaginal intercourse with an infected man. [ 30 ]


A mother may transmit gonorrhea to her newborn during childbirth; when affecting the infant's eyes, it is referred to as  ophthalmia neonatorum . [ 19 ]  It may be able to spread through the objects contaminated with body fluid from an infected person. [ 31 ]  The bacteria typically does not survive long outside the body, typically dying within minutes to hours. [ 32 ]


It is discovered that sexually active women younger than 25 and men who have sex with men are at increased risk of getting gonorrhea. [ 33 ]


Other risk factors include:


Untreated gonorrhea can lead to major complications, such as:


Traditionally, gonorrhea was diagnosed with  Gram stain  and  culture ; however, newer  polymerase chain reaction  (PCR)-based testing methods are becoming more common. [ 20 ] [ 35 ]  If initial treatment fails, a culture should be done to determine the sensitivity of the bacteria to antibiotics. [ 36 ]


Tests that use PCR (aka nucleic acid amplification) to identify genes unique to  N. gonorrhoeae  are recommended for screening and diagnosis of gonorrhea infection. These PCR-based tests require a sample of urine, urethral swabs, or cervical/vaginal swabs. Culture (growing colonies of bacteria in order to isolate and identify them) and Gram-stain (staining of bacterial cell walls to reveal morphology) can also be used to detect the presence of  N. gonorrhoeae  in all specimen types except urine. [ 37 ] [ 38 ]  Studies of the swab sample method for gonorrhea infections have not shown any difference in the number of patients treated, whether the sample was collected at home or in the clinic. The implications for number of patients cured, reinfection rates, partner management, and safety are unknown. [ 39 ]


If Gram-negative, oxidase-positive diplococci are visualized on direct Gram stain of urethral pus (male genital infection), no further testing is needed to establish the diagnosis of gonorrhea infection. [ 40 ] [ 41 ]  However, direct Gram stain of cervical swabs is not useful because the  N. gonorrhoeae  organisms are less concentrated in these samples. The chance of a false positive test is also higher for a cervical swab, as Gram-negative diplococci native to the normal vaginal flora cannot be distinguished from  N. gonorrhoeae  in that context. Thus, cervical swabs must be cultured under the conditions described above. If oxidase positive, Gram-negative diplococci are isolated from a culture of a cervical/vaginal swab specimen, then the diagnosis is made. Culture is especially useful for diagnosis of infections of the throat, rectum, eyes, blood, or joints—areas where PCR-based tests are not well established in all labs. [ 41 ] [ 42 ]  Culture is also useful for antimicrobial sensitivity testing, analyzing treatment failure, and epidemiological purposes (outbreaks, surveillance). [ 41 ]


In patients who may have disseminated gonococcal infection (DGI), all possible mucosal sites should be cultured (e.g., pharynx, cervix, urethra, rectum). [ 42 ]  Three sets of blood cultures should also be obtained. [ 43 ]   Synovial fluid  should be collected in cases of  septic arthritis . [ 42 ]


All people testing positive for gonorrhea should be tested for other sexually transmitted infections such as  chlamydia ,  syphilis , and  human immunodeficiency virus . [ 36 ]  Studies have found co-infection with chlamydia ranging from 46 to 54% in young people with gonorrhea. [ 44 ] [ 45 ]  Among persons in the United States between 14 and 39 years of age, 46% of people with gonorrheal infection also have chlamydial infection. [ 46 ]  For this reason, gonorrhea and chlamydia testing are often combined. [ 37 ] [ 47 ] [ 48 ]  People diagnosed with gonorrhea infection have a fivefold increase risk of HIV transmission. [ 49 ]  Additionally, infected persons who are HIV positive are more likely to shed and transmit HIV to uninfected partners during an episode of gonorrhea. [ 50 ]


The  United States Preventive Services Task Force  (USPSTF) recommends screening for gonorrhea in women at increased risk of infection, which includes all sexually active women younger than 25 years. Extragenital gonorrhea and chlamydia are highest in  men who have sex with men  (MSM). [ 51 ]  Additionally, the USPSTF also recommends routine screening in people who have previously tested positive for gonorrhea or have multiple sexual partners and individuals who use condoms inconsistently, provide sexual favors for money, or have sex while under the influence of alcohol or drugs. [ 18 ]


Screening for gonorrhea in women who are (or intend to become) pregnant, and who are found to be at high risk for  sexually transmitted infections , is recommended as part of  prenatal care in the United States . [ 52 ]


As with most sexually transmitted infections, the risk of infection can be reduced significantly by the correct use of  condoms ,  not having sex , or can be removed almost entirely by limiting sexual activities to a mutually monogamous relationship with an uninfected person. [ 53 ] [ 54 ]


Those previously infected are encouraged to return for follow up care to make sure that the infection has been eliminated. In addition to the use of phone contact, the use of email and text messaging have been found to improve the re-testing for infection. [ 55 ]


Newborn babies coming through the birth canal are given  erythromycin  ointment in the eyes to prevent blindness from infection. The underlying gonorrhea should be treated; if this is done then usually a good prognosis will follow. [ 56 ]


Antibiotics are used to treat gonorrhea infections. As of 2016, both  ceftriaxone  by injection and  azithromycin  by mouth are most effective. [ 4 ] [ 57 ] [ 58 ] [ 59 ]  However, due to increasing rates of  antibiotic resistance , local susceptibility patterns must be taken into account when deciding on treatment. [ 36 ] [ 60 ]   Ertapenem  is a potential effective alternative treatment for ceftriaxone-resistant gonorrhea. [ 61 ] [ 62 ]


Adults may have eyes infected with gonorrhoea and require proper personal hygiene and medications. [ 56 ]  Addition of topical antibiotics have not been shown to improve cure rates compared to oral antibiotics alone in treatment of eye infected gonorrhea. [ 63 ]  For newborns,  erythromycin  ointment is recommended as a preventative measure for gonococcal infant  conjunctivitis . [ 64 ]


Infections of the throat can be especially problematic, as antibiotics have difficulty becoming sufficiently concentrated there to destroy the bacteria. This is amplified by the fact that pharyngeal gonorrhoea is mostly asymptomatic, and gonococci and commensal  Neisseria  species can coexist for long time periods in the pharynx and share anti-microbial resistance genes. Accordingly, an enhanced focus on early detection (i.e., screening of high-risk populations, such as men who have sex with men,  PCR testing  should be considered) and appropriate treatment of pharyngeal gonorrhoea is important. [ 4 ]


It is recommended that sexual partners be tested and potentially treated. [ 36 ]  One option for treating sexual partners of people infected is  patient-delivered partner therapy  (PDPT), which involves providing prescriptions or medications to the person to take to his/her partner without the health care provider's first examining him/her. [ 65 ]


The United States'  Centers for Disease Control and Prevention  (CDC) currently recommend that individuals who have been diagnosed and treated for gonorrhea avoid sexual contact with others until at least one week past the final day of treatment in order to prevent the spread of the bacterium. [ 66 ]


Many antibiotics that were once effective including  penicillin ,  tetracycline , and  fluoroquinolones  are no longer recommended because of high rates of resistance. [ 36 ]  Resistance to  cefixime  has reached a level such that it is no longer recommended as a first-line agent in the United States, and if it is used a person should be tested again after a week to determine whether the infection still persists. [ 57 ]  Public health officials are concerned that an emerging pattern of resistance may predict a global epidemic. [ 67 ] [ 68 ]  In 2016, the  WHO  published new guidelines for treatment, stating "There is an urgent need to update treatment recommendations for gonococcal infections to respond to changing antimicrobial resistance (AMR) patterns of  N. gonorrhoeae . High-level resistance to previously recommended quinolones is widespread and decreased susceptibility to the extended-spectrum (third-generation) cephalosporins, another recommended first-line treatment in the 2003 guidelines, is increasing and several countries have reported treatment failures." [ 69 ]


Gonorrhea if left untreated may last for weeks or months with higher risks of complications. [ 19 ]  One of the complications of gonorrhea is systemic dissemination resulting in skin  pustules  or  petechia ,  septic arthritis ,  meningitis , or  endocarditis . [ 19 ]  This occurs in between 0.6 and 3% of infected women and 0.4 and 0.7% of infected men. [ 19 ]


In men,  inflammation of the epididymis ,  prostate gland , and  urethra  can result from untreated gonorrhea. [ 70 ]  In women, the most common result of untreated gonorrhea is  pelvic inflammatory disease . Other complications include  inflammation of the tissue surrounding the liver , [ 70 ]  a rare complication associated with  Fitz-Hugh–Curtis syndrome ;  septic arthritis  in the fingers, wrists, toes, and ankles;  septic abortion ;  chorioamnionitis  during pregnancy; neonatal or adult blindness from  conjunctivitis ; and  infertility . Men who have had a gonorrhea infection have an increased risk of getting  prostate cancer . [ 24 ]


About 88 million cases of gonorrhea occur each year, out of the 448 million new cases of curable STI each year – that also includes syphilis, chlamydia and  trichomoniasis . [ 11 ]  The prevalence was highest in the  African  region, the  Americas , and Western  Pacific , and lowest in  Europe . [ 71 ]  In 2013, it caused about 3,200 deaths, up from 2,300 in 1990. [ 72 ]


In the United Kingdom, 196 per 100,000 males 20 to 24 years old and 133 per 100,000 females 16 to 19 years old were diagnosed in 2005. [ 19 ]  In 2013, the CDC estimated that more than 820,000 people in the United States get a new gonorrheal infection each year. Fewer than half of these infections are reported to CDC. In 2011, 321,849 cases of gonorrhea were reported to the CDC. After the implementation of a national gonorrhea control program in the mid-1970s, the national gonorrhea rate declined from 1975 to 1997. After a small increase in 1998, the gonorrhea rate has decreased slightly since 1999. In 2004, the rate of reported gonorrheal infections was 113. 5 per 100,000 persons. [ 73 ]


In the US, it is the second-most-common bacterial  sexually transmitted infections ;  chlamydia  remains first. [ 74 ] [ 75 ]  According to the CDC  African Americans  are most affected by gonorrhea, accounting for 69% of all gonorrhea cases in 2010. [ 76 ]


The World Health Organization warned in 2017 of the spread of untreatable strains of gonorrhea, following analysis of at least three cases in Japan, France and Spain, which survived all antibiotic treatment. [ 77 ]


Some scholars translate the biblical terms  zav  (for a male,  Hebrew :  זָב ) and  zavah  (for a female,  זָבָה ) as gonorrhea. [ 78 ]


It has been suggested [ by whom? ]  that  mercury  was used as a treatment for gonorrhea. [ when? ]  Surgeons' tools on board the recovered English warship the  Mary Rose  included a  syringe  that, according to some, was used to inject the mercury via the  urinary meatus  into crewmen with gonorrhea. The name "the clap", in reference to the disease, is recorded as early as the sixteenth century, referring to a medieval  red-light district  in Paris, Les Clapiers. Translating to "The rabbit holes", it was so named for the small huts in which prostitutes worked. [ 79 ] [ 60 ]


Silver nitrate  was one of the widely used drugs in the 19th century. However, it became replaced by  Protargol .  Arthur Eichengrün  invented this type of  colloidal silver , which was marketed by  Bayer  from 1897 onward. The silver-based treatment was used until the first antibiotics came into use in the 1940s. [ 80 ] [ 81 ]


The exact time of onset of gonorrhea as prevalent disease or epidemic cannot be accurately determined from the historical record. One of the first reliable notations occurs in the Acts of the  English Parliament  which, in 1161, passed a law to reduce the spread of "the perilous infirmity of burning". [ 82 ]  The symptoms described are consistent with, but not diagnostic of, gonorrhea. A similar decree was passed by  Louis IX  in France in 1256, replacing regulation with banishment. [ 83 ]  Similar symptoms were noted at the  siege of Acre  by  Crusaders .


Coincidental to, or dependent on, the appearance of a gonorrhea epidemic, several changes occurred in European medieval society. Cities hired  public health  doctors to treat affected patients without right of refusal.  Pope Boniface VIII  rescinded the requirement that physicians complete studies for the lower orders of the  Catholic priesthood . [ 84 ]


Medieval public health physicians in the employ of their cities were required to treat prostitutes infected with the "burning", as well as  lepers  and other epidemic patients. [ 85 ]  After Pope Boniface completely secularized the practice of medicine, physicians were more willing to treat a sexually transmitted infection. [ 84 ]


A vaccine for gonorrhea has been developed that is effective in mice. [ 86 ]  It will not be available for human use until further studies have demonstrated that it is both safe and effective in the human population. Development of a vaccine has been complicated by the ongoing evolution of resistant strains and  antigenic variation  (the ability of  N. gonorrhoeae  to disguise itself with different surface markers to evade the immune system). [ 60 ]


As  N. gonorrhoeae  is closely related to  N. meningitidis  and they have 80–90% homology in their genetic sequences some cross-protection by  meningococcal vaccines  is plausible. A study published in 2017 showed that  MeNZB  group B meningococcal vaccine provided a partial protection against gonorrhea. [ 87 ]  The vaccine efficiency was calculated to be 31%. [ 88 ]  In June 2023,  GlaxoSmithKline  won fast-track designation from the  Food and Drug Administration  for its vaccine candidate against gonorrhea. [ 89 ]


Neisseria gonorrhoeae , also known as  gonococcus  (singular) or  gonococci  (plural), is a species of  Gram-negative   diplococci   bacteria  first isolated by  Albert Neisser  in 1879. [ 3 ]  An  obligate human pathogen, it primarily colonizes the mucosal lining of the urogenital tract; however, it is also capable of adhering to the mucosa of the nose, [ 4 ]  pharynx, rectum, and  conjunctiva . [ 5 ]  It causes the  sexually transmitted  genitourinary infection  gonorrhea [ 6 ]  as well as other forms of gonococcal disease including disseminated gonococcemia,  septic arthritis , and gonococcal ophthalmia neonatorum.


N. gonorrhoeae  is  oxidase  positive and a  microaerophile  that is capable of surviving  phagocytosis  and growing inside  neutrophils . [ 6 ]   Culturing  it requires carbon dioxide supplementation and enriched agar ( chocolate agar ) with various antibiotics ( Thayer–Martin ). It exhibits  antigenic variation  through  genetic recombination  of its  pili  and surface proteins that interact with the  immune system . [ 3 ]


Sexual transmission is through vaginal, anal, or oral sex. [ 7 ]  Sexual transmission may be prevented through the use of barrier protection. [ 8 ]  Perinatal transmission may occur during childbirth, though it is preventable through antibiotic treatment of the mother before birth and application of antibiotic eye gel on the eyes of the newborn. [ 8 ]  Gonococcal infections do not result in protective immunity; therefore, individuals may be infected multiple times. Reinfection is possible due to  N. gonorrhoeae's  ability to evade the immune system by varying its surface proteins. [ 9 ]


Asymptomatic infection is common in both males and females. [ 8 ] [ 10 ]  Untreated infection may spread to the rest of the body (disseminated gonorrhea infection), especially the joints (septic arthritis). Untreated infection in women may cause  pelvic inflammatory disease  and possible infertility due to the resulting scarring. [ 11 ]  Gonorrhoea  is diagnosed through  cultures ,  Gram staining , or  nucleic acid tests  (i.e.  polymerase chain reaction ) of urine samples, urethral swabs, or cervical swabs. [ 12 ] [ 13 ]   Chlamydia  co-testing and testing for other STIs is recommended due to high rates of co-infection. [ 14 ]


Antibiotic resistance in  N. gonorrhoeae  is a growing public health concern, especially given its propensity to develop resistance easily. [ 15 ]  This ability of  N. gonorrhoeae  to rapidly adapt to novel antimicrobial treatments has been seen several times since the 1930s, making numerous treatment plans obsolete. Some strains have  exhibited resistance to the current ceftriaxone treatments. [ 16 ]


Neisseria  species are  fastidious , Gram-negative cocci (though some species are rod-shaped and occur in pairs or short chains) that require nutrient supplementation to grow in laboratory cultures. [ 18 ]  They are facultative intracellular pathogens, meaning they are able to persist and colonize within host cells but can also multiply outside  the host cellular environment. [ 19 ] [ 20 ] [ 21 ]  They typically appear in pairs (diplococci), resembling the shape of coffee beans. [ 21 ]  Members of this genus do not form endospores and are nonmotile, with the exception of pathogenic species, which capable of moving using  twitching motility ; [ 22 ]  most are also  obligate aerobes . [ 23 ] [ 24 ]  Of the 17 species that colonize humans, only two are pathogenic:  N. gonorrhoeae,  which causes gonorrhea, and  N. meningitidis , a leading cause of  bacterial meningitis . [ 25 ] [ 26 ]


N. gonorrhoeae  can be isolated on  Thayer–Martin agar  (or VPN) agar in an atmosphere enriched with 3-7% carbon dioxide. [ 12 ]  Thayer–Martin agar is a chocolate  agar plate  (heated blood agar) containing nutrients and  antimicrobials  ( vancomycin ,  colistin ,  nystatin , and  trimethoprim ). This agar preparation facilitates the growth of  Neisseria  species while inhibiting the growth of contaminating bacteria and fungi. Martin Lewis and  New York City agar  are other types of selective chocolate agar commonly used for  Neisseria  growth. [ 12 ]   N. gonorrhoeae  is  oxidase  positive (possessing cytochrome c oxidase) and  catalase  positive (able to convert hydrogen peroxide to oxygen). [ 12 ]  When incubated with the carbohydrates lactose,  maltose ,  sucrose , and  glucose ,  N. gonorrhoeae  will oxidize only the glucose. [ 12 ]


Unlike other  Neisseria  species that can also metabolize maltose,  N. gonorrhoeae  is capable of using only glucose, pyruvate, and lactate as central carbon sources, and glucose is catabolized via both the  Entner-Doudoroff  (ED) and  pentose phosphate  (PP) pathways,and the ED pathway is the primary oxidative method. [ 19 ] [ 27 ]  Use of these pathways is necessary as  N. gonorrhoeae  is incapable of glucose catabolism via the  Embden-Meyerhof-Parnas  (EMP) pathway due its lack of the phosphofructokinase (PFK) gene; however, the fructose 1,6-bisphosphatase enzyme is present to allow for  gluconeogenesis  to occur. [ 19 ]


Glucose is first metabolized through the ED pathway to produce pyruvate and glyceraldehyde 3-phosphate, the latter of which can then further metabolized by enzymes of the EMP pathway to yield another molecule of pyruvate. [ 28 ]  The resultant pyruvate molecules are then converted into  acetyl-CoA , which can then be incorporated as a substrate for the  citric acid cycle  (CAC) to yield high-energy electron carriers that will be used by the  electron transport chain  (ETC) for ATP production; however,  the CAC is largely used for generating biosynthetic precursors rather than for catabolic purposes. [ 19 ] [ 29 ]  This is due in part to inhibited expression of several CAC enzymes in the presence of glucose, pyruvate, or lactate. These enzymes, namely  citrate synthase ,  aconitase , and  isocitrate dehydrogenase , are needed for the incorporation of acetate. Instead, a partial CAC has been observed, where α-ketoglutarate is formed by  glutamate dehydrogenase  or transamination of oxaloacetate and glutamate by  aspartate aminotransferase  (yielding aspartate and α-ketoglutarate). [ 27 ] [ 29 ]  The CAC then continues from there to yield oxaloacetate, which is an important precursor molecule for a number of biosynthetic pathways. [ 29 ]  Another differentiating aspect of the gonococcal CAC is the lack of malate dehydrogenase, which is instead replaced by a membrane-bound malate:quinone-oxidoreductase that operates independently of NAD +  by directly transferring electrons to ubiquinone. [ 19 ]


Conversely, acetyl-CoA that does not enter the CAC but enters the  phosphotransacetylase - acetate kinase  (PTA-AckA) pathway, where it can be converted into acetate by phosphorylation (to form acetyl phosphate and release coenzyme A) and dephosphorylation to form ATP. [ 30 ]  While this acetate can enter the CAC for further oxidation, this does not occur so long as other carbon sources such as glucose or lactate are present, in which case it is excreted from the cell or incorporated for lipid synthesis. [ 28 ] [ 31 ]   N. gonorrhoeae  lack the  glyoxylate shunt , preventing them from using acetate to form CAC intermediates to replenish the cycle. [ 28 ] [ 27 ]


A significant portion of the glyceraldehyde 3-phosphate formed in gonococci is recycled via the gluconeogenic pathway to reform glucose 6-phosphate, as well as the intermediate fructose 6-phosphate. Both of these can then be used for pentose synthesis in the PP pathway via the oxidative and non-oxidative pathways, respectively, for subsequent nucleotide formation as well as energy production. [ 27 ]


N. gonorrhoeae , like other pathogenic members of the genus  Neisseria , are   capnophiles , meaning they require higher-than-normal concentrations of carbon dioxide (CO 2 ) to grow , either in the form of CO 2  or bicarbonate (HCO 3 - ) depending on the bacterial strain. This requirement must be met exogenously during the lag and stationary growth phases, though it appears to be met through high metabolic CO 2  productions in the exponential phase. Assimilation of this CO 2  in  Neisseria  species is done by  carbonic anhydrase  and phosphoenolpyruvate enzymes in the periplasmic space and the cytoplasm, respectively. [ 27 ]


Lactate catabolism is also of particular importance for gonococci, both for pathogenicity and for growth. [ 19 ]  External lactate is transported in to the cell via lactate permease (LctP). [ 19 ]  The  N. gonorrhoeae  genome encodes for three  lactate dehydrogenase  (LDH) enzymes for that allow for metabolism of both  L -lactate and  D -lactate: a cytoplasmic  NAD + -dependent  D -lactate dehydrogenase (LdhA), which is responsible for and two membrane-bound LDHs, one specific to  L -lactate (LldD) and the other specific to  D -lactate (LdhD). [ 19 ] [ 32 ]  The membrane-bound LDHs have been determined to be  flavoprotein -containing respiratory enzymes that directly oxidize lactate to reduce  ubiquinone . While these enzymes do not directly pump protons (H +  ions) into the periplasmic space, it is proposed that the reduction of ubiquinone by these enzymes is capable of feeding into the larger ETC. [ 32 ]


As an obligate human pathogen and a facultative anaerobic capnophile,  Neisseria gonorrhoeae  typically colonize mucosal surfaces in microaerobic environments, such as those in the genitourinary tract. [ 19 ]  Growth in areas where oxygen concentrations are limited requires a terminal oxidase with a high affinity for oxygen; in gonococci, oxygen reduction is performed by a  ccb 3  -type cytochrome oxidase. In addition to aerobic respiration, gonococci can also perform anaerobic respiration via the reduction of nitrite (NO 2 ) to nitric oxide (NO) as well as reduction of NO to nitrous oxide (N 2 O). [ 19 ] [ 33 ]


There are several enzymes that contribute electrons to the intramembranous ubiquinone pool, the first step in the ETC. These include the membrane bound LDHs (LldD and LdhD),  NADH:ubiquinone oxidoreductase  (aka NADH dehydrogenase; Nuo complex I), Na + -translocating NADH dehydrogenase (Nqr),  succinate dehydrogenase  (SDH), and the membrane-bound NAD + -independent malate:quinone-oxidoreductase (MqR). [ 19 ]


Following the initial transfer of electrons to ubiquinone, proposed schematics for the organization of the gonococcal ETC suggest the electrons can be further passed down the chain by reduction of the  cytochrome  bc 1  complex  or can be directly transferred to NO as a terminal electron acceptor by  NO reductase  (NorB). [ 19 ] [ 34 ]  In the case of the former, electrons can then be passed from the  bc 1  complex along two alternative pathways via the reduction of either cytochrome  c 4  or  c 5 . Both of these cytochromes  transfer electrons to the terminal cytochrome  ccb 3  oxidase for the reduction of O 2  to form H 2 O under aerobic conditions. [ 19 ] [ 33 ]


Gonococci are also reduce NO 2  via an inducible outer membrane-attached copper-containing  nitrite reductase  (AniA, a member of the NirK protein family) under anaerobic conditions, though this process has also been noted in microaerobic conditions as a means of supplementing growth. [ 34 ]  This leads to the formation of NO that is subsequently reduced to N 2 O in a partial denitrification pathway. [ 19 ] [ 33 ] [ 34 ]  The  ccb 3  oxidase of  N. gonorrhoeae , dissimilarly to other members of the  Neisseria  genus, is a tri-heme protein that can transfer electrons not only to O 2  (conserved across  Neisseria  species) but also to AniA for NO 2  reduction. This  is in addition to the typical process of receiving electrons transferred from cytochrome  c 5 . [ 34 ] [ 35 ]


The general purpose of the ETC is the formation of the electrochemical gradient of hydrogen ions (H +  or protons), resulting from concentration differences across the plasma membrane, needed to power ATP production in a process known as  oxidative phosphorylation . [ 36 ]  In gonococci, movement of protons into the periplasmic space is accomplished by the Nuo complex I, the cytochrome  bc 1  complex, and cytochrome  ccb 3 . [ 19 ] [ 34 ] [ 37 ]  Subsequently, ATP synthesis is performed by the  F 1 F 0  ATP synthase , a two-part protein complex present in gonococci as well as numerous other species across phylogenetic domains. [ 38 ]  This complex couples proton translocation back into the cytoplasm along its gradient with mechanical rotation to generate ATP. [ 39 ]


The general purpose of the ETC is the formation of the electrochemical gradient of hydrogen ions (H +  or protons), resulting from concentration differences across the plasma membrane, needed to power ATP production in a process known as  oxidative phosphorylation . [ 40 ]  In gonococci, movement of protons into the periplasmic space is accomplished by the Nuo complex I, the cytochrome  bc 1  complex, and cytochrome  ccb 3 . [ 19 ] [ 34 ] [ 41 ]  Subsequently, ATP synthesis is performed by the  F 1 F 0  ATP synthase , a two-part protein complex present in gonococci as well as numerous other species across phylogenetic domains. [ 42 ]  This complex couples proton translocation back into the cytoplasm along its gradient with mechanical rotation to generate ATP. [ 43 ]


To acquire the necessary iron, gonococci produce TonB-dependent transporters (TDTs) on the surface of their outer membrane that are able to directly extract iron, along with other metals, from their respective carrier proteins. Some of these include transferrin binding proteins A (TbpA) and B (TbpB), lactoferrin-binding proteins A (LbpA) and B (LbpB), and hemoglobin/hemoglobin-haptoglobin binding proteins HpuB and HpuA. [ 19 ] [ 44 ]  In addition to these proteins, gonococci are also capable of using  siderophores , or compounds that are capable of chelating iron in the environment, that are produced by other bacteria; however, gonococcal cells are incapable of synthesizing siderophores themselves. These xenosiderophores are taken up by the TDT FetA through the outer membrane and then brought into the cell by the  fetBCDEF  transporter system. [ 19 ] [ 44 ]


Along with the sequestration defence that can be further upregulated by host inflammation, humans also produce  siderocalins  that are able to chelate siderophores to as a further method of inhibiting pathogenic bacterial growth. These are sometimes ineffective against  N. gonorrhoeae , which is able to colonize intracellularly, particularly in phagocytic cells such as  macrophages  and neutrophils. Increases in host intracellular iron also down regulates some of the intracellular pathogen-killing mechanisms; coincidentally, pathogenic  Neisseria  are able to alter several host cell mechanisms that ultimately allow the pathogen to take most of the available iron away from the host immune cell. [ 44 ]


On its surface,  N. gonorrhoeae  bears hair-like  pili , surface proteins with various functions, and sugars called  lipooligosaccharide . The pili mediate adherence, movement, and DNA exchange. The opacity-associated (Opa) proteins interact with the immune system, as do the  porins . Lipooligosaccharide is an  endotoxin  that provokes an immune response. All of these are  antigenic  and exhibit  antigenic variation . The pili, Opa proteins, porins, and even the lipooligosaccharide have mechanisms to inhibit the immune response, making asymptomatic infection possible. [ 45 ]


Phase-variable opacity-associated (Opa) adhesin proteins are used by  N. gonorrhoeae  as part of evading immune response in a host cell. At least 12 Opa proteins are known and the many variations of surface proteins make recognizing  N. gonorrhoeae  and mounting a defense by immune cells more difficult. [ 46 ]  Opa proteins are  in the outer membrane and facilitate a response when the bacteria interacts with a variety of host cells. These proteins bind to various epithelial cells, and allow  N. gonorrhoeae  to increase the length of infection as well as increase the amount of invasion into other host cells. [ 47 ]


Dynamic  polymeric  protein filaments called  type IV pili  allow  N. gonorrhoeae  to do many bacterial processes including adhesion to surfaces, transformation competence, twitching motility, and immune response evasions. [ 19 ]  To enter the host the bacteria uses the pili to adhere to and penetrate mucosal surfaces. The pili are a pivotal  virulence factor  for  N. gonorrhoeae ; without them, the bacterium is unable to promote colonization. [ 48 ]  For motility, individual bacteria use their pili in a manner that resembles a grappling hook: first, they are extended from the cell surface and attach to a  substrate . Subsequent pilus retraction drags the cell forward. The resulting movement is referred to as twitching motility.  N. gonorrhoeae  is able to pull 100,000 times its own weight, [ 49 ]  and the pili used to do so are amongst the strongest biological motors known to date, exerting one  nanonewton . [ 49 ]  The PilF and PilT  ATPase  proteins are responsible for powering the extension and retraction of the type IV pilus, respectively. The adhesive functions of the gonococcal pilus play a role in  microcolony  aggregation and  biofilm  formation. These pili are also used to avoid immune responses from the cell they are invading by having their type IV pili antigenically vary. The main pilus filament is replaced by variable DNA sequences very frequently. [ 19 ]  By doing this process rapidly, they are able to create a diversity of pili on their surface and evade the host cell's immune response. [ 48 ]


Lipooligosaccharide is a low-weight version of lipopolysaccharide present on the surfaces of most other Gram-negative bacteria. It is a sugar (saccharide) side chain attached to lipid A (thus "lipo-") in the outer membrane coating the cell wall of the bacteria. The root "oligo" refers to the fact that it is a few sugars shorter than the typical lipopolysaccharide. [ 6 ]  As an endotoxin, it provokes inflammation. The shedding of lipooligosaccharide by the bacteria are sometimes responsible for issues associated with pelvic inflammatory disease. [ 6 ]  Although it functions primarily as an endotoxin, lipooligosaccharide may disguise itself with host  sialic acid  and block initiation of the  complement cascade . [ 6 ]


N. gonorrhoeae  evades the immune system through a process called  antigenic variation . [ 50 ]  This process allows  N. gonorrhoeae  to recombine its genes and alter the  antigenic determinants  that adorn its surface, [ 6 ]  such as the Type IV pili. [ 51 ]  Simply stated, the chemical composition of molecules are changed due to changes at the genetic level. [ 9 ]   N. gonorrhoeae  is able to vary the composition of its pili and lipooligosaccharide. Of these, the pili exhibit the most antigenic variation due to chromosomal rearrangement. [ 11 ] [ 6 ]  The  pilS  gene is an example of this ability to rearrange, as its combination with the  pilE  gene is estimated to produce over 100 variants of the PilE protein. [ 9 ]  These changes allow for adjustment to local environmental differences at the site of infection, evasion of recognition by targeted antibodies, and inhibit the formation of an effective vaccine. [ 9 ]


In addition to gene rearrangement, it is also  naturally competent , meaning it can acquire extracellular DNA from the environment via its type IV pilus, specifically proteins PilQ and PilT. [ 52 ]  These processes allow  N. gonorrhoeae  to acquire and spread new genes, disguise itself with different surface proteins, and prevent the development of  immunological memory  – an ability which has contributed to antibiotic resistance and impeded vaccine development. [ 53 ]


Phase variation  is similar to antigenic variation, but instead of changes at the genetic level altering the composition of molecules, these genetic changes result in the activation or deactivation of a gene. [ 9 ]  Phase variation most often arises from a  frameshift  in the expressed gene. [ 9 ]  The Opa proteins of  N. gonorrhoeae  rely strictly on phase variation. [ 9 ]  Every time the bacteria replicate, they may switch multiple Opa proteins on or off through  slipped-strand mispairing . That is, the bacteria introduce frameshift mutations that bring genes in or out of frame. The result is that different Opa genes are translated every time. [ 6 ]  Pili are varied by antigenic variation, but also phase variation. [ 9 ]  Frameshifts occur in both the  pilE  and  pilC  genes, effectively turning off the expression of pili in situations when they are not needed, such as during intracellular colonization as opposed to extracellular mucosal cell surface adhesion. [ 9 ]


After gonococci invade and  transcytose  the host epithelial cells, they land in the submucosa, where neutrophils promptly consume them. [ 6 ]  The pili and Opa proteins on the surface may interfere with phagocytosis, [ 11 ]  but most gonococci end up in neutrophils. The exudates from infected individuals contain many neutrophils with ingested gonococci. Neutrophils release an oxidative burst of  reactive oxygen species  in their phagosomes to kill the gonococci. [ 54 ]  However, a significant fraction of the gonococci can resist killing through the action of their  catalase [ 6 ]  which breaks down reactive oxygen species and is able to reproduce within the neutrophil phagosomes. [ 55 ]


The bacterial RecA protein, which mediates repair of DNA damage, plays an important role in gonococcal survival. [ 56 ]   N. gonorrhoeae  may replace DNA damaged in neutrophil phagosomes with DNA from neighboring gonococci. [ 57 ]  The process in which recipient gonococci integrate DNA from neighboring gonococci into their genome is called transformation. [ 58 ]


The genomes of several strains of  N .  gonorrhoeae  have been sequenced. Most of them are about 2.1 Mb in size and encode 2,100 to 2,600 proteins (although most seem to be in the lower range). [ 59 ]  For instance, strain NCCP11945 consists of one circular chromosome (2,232,025 bp) encoding 2,662 predicted  open reading frames  (ORFs) and one  plasmid  (4,153 bp) encoding 12 predicted ORFs. The estimated coding density over the entire genome is 87%, and the average G+C content is 52.4%, values that are similar to those of strain FA1090. The NCCP11945 genome encodes 54 tRNAs and four copies of 16S-23S-5S rRNA operons. [ 60 ]


Horizontal gene transfer , also termed lateral gene transfer, is the sharing of genetic information amongst living organisms. [ 61 ]  This transmission of information is a driving force of antibiotic resistance in  N. gonorrhoeae . [ 62 ]   [ 63 ]   Studies have identified that  N. gonorrhoeae  has obtained methods of antimicrobial resistance by way of horizontal gene transfer from other  Neisseria  species including  N.   lactamica ,  N. macacae , and  N. mucosa.   [ 64 ]


Transformation in  N. gonorrhoeae  is performed by the type IV pilus, where the DNA is bound and brought into the cell, followed by processing and homologous recombination. [ 65 ]


Found in some genomes of  Neisseria gonorrhoeae , the gonococcal genetic island (GGI), a  genomic island  (GI) specific to gonococci, has been identified as a mobile genetic element that is horizontally acquired. [ 66 ]   [ 67 ]  GGI is involved with antimicrobial resistance, transmission of genetic information, and iron acquisition. [ 66 ]  The genes within the gonococcal genetic island encode for the infamous  type IV secretion system  (T4SS), which is responsible for DNA secretion and is essential for biofilm formation.  [ 66 ] [ 68 ]


In 2011, researchers at Northwestern University found evidence of a human DNA fragment in a  N. gonorrhoeae  genome, the first example of horizontal gene transfer from humans to a bacterial pathogen. [ 69 ] [ 70 ]


Symptoms of infection with  N. gonorrhoeae  differ depending on the site of infection and many infections are asymptomatic independent of sex. [ 71 ] [ 45 ] [ 7 ]  Depending on the route of transmission,  N. gonorrhoeae  may cause infection of the throat ( pharyngitis ) or infection of the anus/rectum ( proctitis ). [ 72 ] [ 11 ]


Disseminated gonococcal infections can occur when  N. gonorrhoeae  enters the bloodstream, often spreading to the joints and causing a rash (dermatitis-arthritis syndrome). [ 72 ]  Dermatitis-arthritis syndrome results in joint pain ( arthritis ), tendon inflammation ( tenosynovitis ), and painless non- pruritic  (non-itchy)  dermatitis . [ 11 ]  Disseminated infection and pelvic inflammatory disease in women tend to begin after  menses  due to reflux during menses, facilitating spread. [ 72 ]  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 ). [ 72 ] [ 73 ]


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. [ 72 ]  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 ). [ 72 ] [ 11 ] [ 74 ]


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. [ 72 ]  Pelvic inflammatory disease develops in 10 to 20% of the females infected with  N. gonorrhoeae . [ 72 ]


In  perinatal infection , the primary manifestation is infection of the eye (neonatal conjunctivitis or  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. [ 72 ] [ 73 ]  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. [ 73 ] [ 72 ]


N. gonorrhoeae  is most often transmitted through vaginal, oral, or anal sex; nonsexual transmission is unlikely in adult infection. [ 7 ]  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. [ 7 ]  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. [ 75 ]


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. [ 76 ]


Successful transmission is followed by adherence to the  epithelial cells  found at the infected mucosal site by the bacterium's  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. [ 15 ]  Post attachment,  N. gonorrhoeae  replicates its genome and divides to form  microcolonies . [ 15 ]  Gonococcal infection is sometimes aided by the membrane cofactor protein, CD46, as it has been known to act as a receptor for gonococcal pilus. [ 45 ]   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. [ 45 ]  During growth and colonization,  N. gonorrhoeae  stimulates the release of  pro-inflammatory   cytokines  and  chemokines  from host immune cells that result in the recruitment of  neutrophils  to the area. [ 9 ]  These  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. [ 9 ]


The primary detection methods for  Neisseria gonorrhoeae  are  nucleic acid amplification tests , which are the most sensitive techniques available. [ 77 ] [ 78 ]  Other methods of detection include microscopy and culture. [ 77 ]


Transmission is reduced by using latex barriers (e.g.  condoms  or  dental dams ) during sex and by limiting sexual partners. [ 8 ]  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. [ 6 ]


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. [ 79 ]  There are problems that have hampered vaccine development including: the absence of immunity post-infection, exclusively human hosts, and  antigenic  and  phase variation  of potential vaccine targets. [ 80 ]  Currently, there are several  N. gonorrhoeae  vaccines in development including an outer membrane vesicle vaccine. [ 80 ]  This includes the NGoXIM, the native OMV, and Bexsero/4CMenB vaccine candidates, which are all in the late clinical stages of development. [ 81 ]  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. [ 80 ]


Currently, the  CDC  recommends a single dose of the injectable  cephalosporin ,  ceftriaxone , as the first line of defense against gonococcal infections. [ 82 ]  Individuals weighing less than 150 kg are typically prescribed a ceftriaxone concentration of 500 mg, while individuals who weigh over 150 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. [ 79 ]  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 mg, along with 2 g of azithromycin taken orally. [ 79 ]  If an individual is not allergic to cephalosporins but ceftriaxone is unavailable, an alternative treatment is a single dose of 800 mg cefixime consumed orally. [ 79 ]  In all of these cases, combination therapy and co-treatment for chlamydia is recommended, as simultaneous infections are common. [ 83 ]


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". [ 84 ] [ 85 ]  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. [ 85 ]


Prior to 2007,  fluoroquinolones  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  cephalosporins  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. [ 86 ]


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 . [ 45 ]  There are three different pathways that activate this system however, they all result in the activation of complement protein 3 (C3). [ 87 ]  A cleaved portion of this protein,  C3b , is deposited on pathogenic surfaces and results in  opsonization  as well as the downstream activation of the  membrane attack complex . [ 87 ]   N. gonorrhoeae  has several mechanisms to avoid this action. [ 15 ]  As a whole, these mechanisms are referred to as serum resistance. [ 15 ]


Neisseria gonorrhoeae  is named for Albert Neisser, who isolated it as the causative agent of the disease gonorrhea in 1878. [ 15 ] [ 3 ]  Galen (130 AD) coined the term "gonorrhea" from the Greek  gonos  which means "seed" and  rhoe  which means "flow". [ 88 ] [ 9 ]  Thus, gonorrhea means "flow of seed", a description referring to the white penile discharge, assumed to be semen, seen in male infection. [ 15 ]


In 1878, Albert Neisser isolated and visualized  N. gonorrhoeae  diplococci in samples of pus from 35 men and women with the classic symptoms of genitourinary infection with gonorrhea – two of whom also had infections of the eyes. [ 9 ]  In 1882, Leistikow and Loeffler were able to grow the organism in culture. [ 15 ]  Then in 1883, Max Bockhart proved conclusively that the bacterium isolated by Albert Neisser was the causative agent of the disease known as gonorrhea by inoculating the penis of a healthy man with the bacteria. [ 9 ]  The man developed the classic symptoms of gonorrhea days after, satisfying the last of  Koch's postulates . Until this point, researchers debated whether syphilis and gonorrhea were manifestations of the same disease or two distinct entities. [ 89 ] [ 9 ]  One such 18th-century researcher, John Hunter, tried to settle the debate in 1767 [ 9 ]  by inoculating a man with pus taken from a patient with gonorrhea. He erroneously concluded that syphilis and gonorrhea were indeed the same disease when the man developed the copper-colored rash that is classic for syphilis. [ 87 ] [ 89 ]  Although many sources repeat that Hunter inoculated himself, [ 87 ] [ 15 ]  others have argued that it was in fact another man. [ 90 ]  After Hunter's experiment other scientists sought to disprove his conclusions by inoculating other male physicians, medical students, [ 15 ]  and incarcerated men with gonorrheal pus, who all developed the burning and discharge of gonorrhea. One researcher, Ricord, took the initiative to perform 667 inoculations of gonorrheal pus on patients of a mental hospital, with zero cases of syphilis. [ 9 ] [ 15 ]  Notably, the advent of penicillin in the 1940s made effective treatments for gonorrhea available. [ 91 ]


Neonatal conjunctivitis  is a form of  conjunctivitis  (inflammation of the outer eye) which affects newborn babies following birth. It is typically due to  neonatal bacterial infection , although it can also be non-infectious (e.g. chemical exposure). [ 1 ]  Infectious neonatal conjunctivitis is typically contracted during  vaginal delivery  from exposure to bacteria from the birth canal, most commonly  Neisseria gonorrhoeae  or  Chlamydia trachomatis . [ 2 ]


Antibiotic ointment is typically applied to the newborn's eyes within 1 hour of birth as prevention for gonococcal ophthalmia. [ 3 ]  This practice is recommended for all newborns and most hospitals in the United States are required by state law to apply eye drops or ointment soon after birth to prevent the disease. [ 4 ] [ 5 ]


If left untreated, neonatal conjunctivitis can cause  blindness .


Neonatal conjunctivitis by definition presents during the first month of life. Signs and symptoms include: [ citation needed ]


Chemical causes: Right after delivery


Neisseria gonorrhoeae : Delivery of the baby until 5 days after birth (early onset)


Chlamydia trachomatis : 5 days after birth to 2 weeks (late onset –  C. trachomatis  has a longer incubation period) [ 2 ]


Untreated cases may develop corneal ulceration, which may perforate, resulting in corneal opacification and staphyloma formation. [ citation needed ]


Historically in Europe, it led to blindness in 3% of cases and accounted for 25–40% of cases of blindness in Germany. [ 6 ]


Chemical irritants such as  silver nitrate  can cause chemical conjunctivitis, usually lasting 2–4 days. Thus, prophylaxis with a 1% silver nitrate solution is no longer in common use. [ 7 ]  In most countries,  neomycin  and  chloramphenicol  eye drops are used, instead. [ 8 ] [ 9 ]
However, newborns can develop neonatal conjunctivitis due to reactions with chemicals in these common eye drops. [ 10 ]  A blocked tear duct may also be another noninfectious cause of neonatal conjunctivitis. [ citation needed ]


The two most common infectious causes of neonatal conjunctivitis are  N. gonorrheae  and  Chlamydia,  typically acquired from the birth canal during delivery. However, other different bacteria and viruses can be the cause, including  herpes simplex virus  (HSV 2),  Staphylococcus aureus ,  Streptococcus pyogenes , and  Streptococcus pneumoniae . [ citation needed ]


Ophthalmia neonatorum due to gonococci ( N. gonorrhoeae ) typically manifests in the first 5 days after birth and is associated with marked bilateral purulent discharge and local inflammation. In contrast, conjunctivitis secondary to infection with  C. trachomatis  produces conjunctivitis 3 days to 2 weeks after delivery. The discharge is usually more watery (mucopurulent) and less inflamed. Babies infected with chlamydia may develop pneumonitis (chest infection) at a later stage (range 2–19 weeks after delivery). Infants with chlamydia pneumonitis should be treated with oral erythromycin for 10–14 days. [ 11 ]


Diagnosis is performed after taking swab from the infected conjunctivae. [ citation needed ]


Antibiotic ointment is typically applied to the newborn's eyes within 1 hour of birth as prevention against gonococcal ophthalmia. [ 3 ]  This may be  erythromycin ,  tetracycline , or rarely  silver nitrate [ 3 ]  or  Argyrol  (mild silver protein). The use of 1-2% silver nitrate solution was introduced in 1881 by  Credé  as  Credé's prophylaxis .  [ 3 ]   [ 12 ] [ 13 ] [ 14 ]


Prophylaxis needs antenatal, natal, and postnatal care.


Systemic therapy: Newborns with gonococcal ophthalmia neonatorum should be treated for 7 days with ceftriaxone,  cefotaxime ,  ciprofloxacin , or crystalline benzyl  penicillin .


The incidence of neonatal conjunctivitis varies widely depending on the geographical location. The incidence in England was 257 (95% confidence interval: 245 to 269) per 100,000 in 2011. [ 20 ]


In late 19th century Europe, the prevalence of opthalmia neonatorum among live births in maternity hospitals exceeded 10%, with blindness in 3% of affected infants. Half of children in blind schools were there because of it  [ 14 ] , and in Germany it accounted for 25-40% of cases of blindness  [ 6 ]


Pelvic inflammatory disease , also known as  pelvic inflammatory disorder  ( PID ), is an  infection  of the upper part of the  female reproductive system , mainly the  uterus ,  fallopian tubes , and  ovaries , and inside of the  pelvis . [ 5 ] [ 2 ]  Often, there may be no symptoms. [ 1 ]  Signs and symptoms, when present, may include lower abdominal pain,  vaginal discharge ,  fever ,  burning with urination ,  pain with sex ,  bleeding after sex , or  irregular menstruation . [ 1 ]  Untreated PID can result in long-term complications including  infertility ,  ectopic pregnancy ,  chronic pelvic pain , and  cancer . [ 2 ] [ 3 ] [ 4 ]


The disease is caused by bacteria that spread from the vagina and cervix. [ 5 ]  It has been reported that infections by  Neisseria gonorrhoeae  or  Chlamydia trachomatis  are present in 75 to 90 percent of cases. [ 2 ]  However, in the UK it is reported by the NHS that infections by  Neisseria gonorrhoeae  and  Chlamydia trachomatis  are responsible for only a quarter of PID cases. [ 9 ]  Often, multiple different bacteria are involved. [ 2 ]


Without treatment, about 10 percent of those with a  chlamydial infection  and 40 percent of those with a  gonorrhea infection  will develop PID. [ 2 ] [ 10 ]  Risk factors are generally similar to those of  sexually transmitted infections  and include a  high number of sexual partners  and  drug use . [ 2 ]   Vaginal douching  may also increase the risk. [ 2 ]  The diagnosis is typically based on the presenting signs and symptoms. [ 2 ]  It is recommended that the disease be considered in all women of childbearing age who have lower abdominal pain. [ 2 ]  A definitive diagnosis of PID is made by finding  pus  involving the fallopian tubes during  surgery . [ 2 ]   Ultrasound  may also be useful in diagnosis. [ 2 ]


Efforts to prevent the disease include  not having sex  or having few sexual partners and using  condoms . [ 6 ]  Screening women at risk for chlamydial infection followed by treatment decreases the risk of PID. [ 11 ]  If the diagnosis is suspected, treatment is typically advised. [ 2 ]  Treating a woman's sexual partners should also occur. [ 11 ]  In those with mild or moderate symptoms, a single injection of the  antibiotic   ceftriaxone  along with two weeks of  doxycycline  and possibly  metronidazole  by mouth is recommended. [ 7 ]  For those who do not improve after three days or who have severe disease, intravenous antibiotics should be used. [ 7 ]


Globally, about 106 million cases of chlamydia and 106 million cases of gonorrhea occurred in 2008. [ 10 ]  The number of cases of PID, however, is not clear. [ 8 ]  It is estimated to affect about 1.5 percent of young women yearly. [ 8 ]  In the United States, PID is estimated to affect about one million people each year. [ 12 ]  A type of  intrauterine device  (IUD) known as the  Dalkon shield  led to increased rates of PID in the 1970s. [ 2 ]  Current IUDs are not associated with this problem after the first month. [ 2 ]


Symptoms in PID range from none to severe. If there are symptoms,  fever ,  cervical  motion tenderness, lower  abdominal pain , new or different discharge,  painful intercourse ,  uterine  tenderness,  adnexal  tenderness, or irregular menstruation may be noted. [ 2 ] [ 1 ] [ 13 ] [ 14 ]


Other complications include  endometritis ,  salpingitis ,  tubo-ovarian abscess , pelvic  peritonitis , periappendicitis, and  perihepatitis . [ 15 ]


PID can cause  scarring  inside the reproductive system, which can later cause serious complications, including chronic pelvic pain,  infertility , ectopic pregnancy (the leading cause of pregnancy-related deaths in adult females), and other complications of pregnancy. [ 16 ]  Occasionally, the infection can spread to the  peritoneum  causing inflammation and the formation of scar tissue on the external surface of the  liver  ( Fitz-Hugh–Curtis syndrome ). [ 17 ]


Chlamydia trachomatis  and  Neisseria gonorrhoeae  are common causes of PID. However,
PID can also be caused by other untreated infections, like bacterial vaginosis. [ 18 ]
Data suggest that PID is often polymicrobial. [ 15 ]  Isolated  anaerobes  and  facultative microorganisms  have been obtained from the upper genital tract.  N. gonorrhoeae  has been isolated from fallopian tubes, facultative and anaerobic organisms were recovered from endometrial tissues. [ 19 ] [ 20 ]


The anatomical structure of the internal organs and tissues of the female reproductive tract provides a pathway for pathogens to ascend from the vagina to the pelvic cavity through the  infundibulum . The disturbance of the naturally occurring vaginal  microbiota  associated with  bacterial vaginosis  increases the risk of PID. [ 19 ]


N. gonorrhoea  and  C. trachomati s are the most common organisms. The least common were infections caused exclusively by anaerobes and facultative organisms. Anaerobes and facultative bacteria were also isolated from 50 percent of the patients from whom  Chlamydia  and  Neisseria  were recovered; thus, anaerobes and facultative bacteria were present in the upper genital tract of nearly two-thirds of the PID patients. [ 19 ]  PCR and serological tests have associated extremely fastidious organism with endometritis, PID, and  tubal factor infertility .  Microorganisms associated with PID are listed below. [ 19 ]


Cases of PID have developed in people who have stated they have never had sex. [ 21 ]


Upon a  pelvic examination ,  cervical motion ,  uterine , or adnexal tenderness will be experienced. [ 5 ]   Mucopurulent  cervicitis  and or  urethritis  may be observed. In severe cases more testing may be required such as  laparoscopy , intra-abdominal bacteria sampling and culturing, or tissue biopsy. [ 15 ] [ 23 ]


Laparoscopy can visualize "violin-string"  adhesions , characteristic of  Fitz-Hugh–Curtis perihepatitis  and other abscesses that may be present. [ 23 ]


Other imaging methods, such as ultrasonography, computed tomography (CT), and magnetic imaging (MRI), can aid in diagnosis. [ 23 ]  Blood tests can also help identify the presence of infection: the erythrocyte sedimentation rate (ESR), the C-reactive protein (CRP) level, and chlamydial and gonococcal DNA probes. [ 15 ] [ 23 ]


Nucleic acid amplification tests (NAATs), direct fluorescein tests (DFA), and enzyme-linked immunosorbent assays (ELISA) are highly sensitive tests that can identify specific pathogens present. Serology testing for antibodies is not as useful since the presence of the microorganisms in healthy people can confound interpreting the antibody titer levels, although antibody levels can indicate whether an infection is recent or long-term. [ 15 ]


Definitive criteria include  histopathologic  evidence of endometritis, thickened filled  fallopian tubes , or  laparoscopic  findings.  Gram stain /smear becomes definitive in the identification of rare, atypical and possibly more serious organisms. [ 24 ]  Two thirds of patients with laparoscopic evidence of previous PID were not aware they had PID, but even asymptomatic PID can cause serious harm.


Laparoscopic identification is helpful in diagnosing tubal disease; a 65 percent to 90 percent  positive predictive value  exists in patients with presumed PID. [ 25 ]


Upon  gynecologic ultrasound , a potential finding is  tubo-ovarian complex , which is  edematous  and dilated pelvic structures as evidenced by vague margins, but without  abscess  formation. [ 26 ]


A number of other causes may produce similar symptoms including appendicitis, ectopic pregnancy, hemorrhagic or ruptured  ovarian cysts ,  ovarian torsion , and endometriosis and  gastroenteritis , peritonitis, and bacterial vaginosis among others. [ 2 ]


Pelvic inflammatory disease is more likely to reoccur when there is a prior history of the infection, recent sexual contact, recent onset of  menses , or an  IUD  (intrauterine device) in place or if the partner has a  sexually transmitted infection . [ 27 ]


Acute pelvic inflammatory disease is highly unlikely when recent intercourse has not taken place or an IUD is not being used. A sensitive serum  pregnancy test  is typically obtained to rule out ectopic pregnancy.  Culdocentesis  will differentiate  hemoperitoneum  (ruptured ectopic pregnancy or  hemorrhagic cyst ) from pelvic  sepsis  (salpingitis, ruptured pelvic abscess, or ruptured appendix). [ 28 ]


Pelvic and vaginal ultrasounds are helpful in the diagnosis of PID. In the early stages of infection, the ultrasound may appear normal. As the disease progresses, nonspecific findings can include free pelvic fluid, endometrial thickening, uterine cavity distension by fluid or gas. In some instances the borders of the uterus and ovaries appear indistinct. Enlarged ovaries accompanied by increased numbers of small cysts correlates with PID. [ 28 ]


Laparoscopy is infrequently used to diagnose pelvic inflammatory disease since it is not readily available.  Moreover, it might not detect subtle inflammation of the fallopian tubes, and it fails to detect endometritis. [ 29 ]   Nevertheless, laparoscopy is conducted if the diagnosis is not certain or if the person has not responded to antibiotic therapy after 48 hours. [ citation needed ]


No single test has adequate  sensitivity  and  specificity  to diagnose pelvic inflammatory disease. A large multisite U.S. study found that cervical motion tenderness as a minimum clinical criterion increases the sensitivity of the  CDC  diagnostic criteria from 83 percent to 95 percent. However, even the modified 2002 CDC criteria do not identify women with subclinical disease. [ 30 ]


Regular testing for  sexually transmitted infections  is encouraged for prevention. [ 31 ]  The risk of contracting pelvic inflammatory disease can be reduced by the following:


Treatment is often started without confirmation of infection because of the serious complications that may result from delayed treatment. Treatment depends on the  infectious agent  and generally involves the use of  antibiotic  therapy although there is no clear evidence of which antibiotic regimen is more effective and safe in the management of PID. [ 34 ]  If there is no improvement within two to three days, the patient is typically advised to seek further medical attention. Hospitalization sometimes becomes necessary if there are other complications.  Treating sexual partners for possible STIs can help in treatment and prevention. [ 11 ]  There should be no wait for STI results to start treatment. Treatment should not be avoided for longer than 2-3 days due to increasing the risk of infertility. [ 35 ]