University of Santo Tomas

Faculty of Pharmacy
A.Y. 2015-2016

Sexually Transmitted
Infections:

Gonorrhea

Submitted to: Agnes L. Castillo, Ph.D., Phar, BS Botany

Submitted by:
PAYURAN, Joselle Anne F.
QUE, Bill A.

Gonorrhea
I.

A. Definition
Gonorrhea is a widespread sexually transmitted infection caused by the organism
Neisseria gonorrhea. It is transmitted solely by sexual contact or perinatally and
affects mostly the mucous membranes of the urethra and cervix and, on several
occasions those of the rectum, oropharynx, and conjunctivae. It is a very common
infection, especially among young people ages 15-24 years old.
Gonorrhea exists as one of the oldest known human diseases, and there are several
references to gonorrhea can be found in ancient Chinese writings, the biblical Old
Testament (Leviticus) and other ancient works. Galen (AD 130), insinuating depiction
of the urethral discharge or exudate as semen, introduced the term gonorrhea, from
the Greek terms gonos and rhoea which means, flow of seed. The descriptive term
running issue from Leviticus 15 might mean urethral exudate of gonorrhea.
Hippocrates made the first scientific observations on gonorrhea and he made use of
the term strangury to delineate acute gonorrhea.
B. Synonyms of the Disease
The most common name for gonorrhea, The Clap, originated from the term
clappoir, which was used for houses of prostitution in Paris in the Middle Ages. The
disease is also called as The Drip, which refers to its symptom that Galen described
as a pus-like discharge. In 1879, the etiologic agent or organism was described by
Albert Neisser and was first cultivated by Leistikow and Leffler in 1882. In the
Philippines, it is called Tulo because of the purulent (pus) discharge commonly
observed in men.

II.

Causative Agent
A. Description and Morphology
Neisseria gonorrhea is a non-spore-forming, non-motile, gram-negative aerobic
coccus that characteristically grows in pairs (diplococci) with adjacent sides flattened
described as either kidney or bean shaped. Although referred as a non-motile
organism because it lacks a flagella but it can move through the extension and
retraction of its type IV pilus. All Neisseria spp. can quickly oxidize

dimethylphenyldiamine or tetramethyl-p-phenylenediamine, the basis of the oxidase

test. The gonococci can be distinguished from other Neisseria spp. by their ability to
grow on selective media; to ferment glucose but not maltose, lactose, or sucrose; and
to reduce nitrites and also their ability to grow well at reduced or impoverished
temperatures or on simple nutrient agar.
B. Virulence Factors
Type IV pili or N-methylphenylalanine (fimbriae) are strong flexible filaments
that extends from the gonococcal cell surface to the outer membrane of the
gonococcus through an integral outer membrane protein called PilQ. The pil gene
complex is responsible for the expression of pili.
Mature pili are composed of multiple protein subunits known as pilin or pilE,
which forms the pilus fiber. Twitching is caused by the activity of the proteins PilT
and PilB, which enable the gonococci to depolymerize and re-polymerize the pilus
strand. The pilin subunit has regions of interstrain antigenic similarity, principally
near the amino terminus, but there are also areas of extreme antigenic variability. A
single strain of the bacteria has the capability to produce pili with different antigenic
compositions, which undermined the utility of pilus-based vaccines for the treatment
of gonorrhea.
There are two types of colonies according to the presence of pilus, the P - type
and P++ type. In the P++ type (formerly called T1 and T2), the organisms have
numerous pili extending from the cell surface, while in the P- type (formerly called
T3 and T4), the colonies lack pili.
The pili serve as the mediatory attachment of the N. gonorrhea to human
mucosal surface. Pili increase the adhesion of the bacteria to the host tissues.
Previous studies suggest that Pil-negative variants are non-infectious.
Pili can contribute to the overall resistance of the bacteria to the killing by
neutrophils in the fallopian tube mucosa model. Pili enable the attachment of the
bacteria to the non-ciliated epithelial cells, which creates a system of transport
through these cells into the intercellular spaces near the basement membrane or
directly into the sub-epithelial space while the nearby ciliated mucosal cells lose their
cilia and are shed away.
Other outer membrane structures play important roles in the attachment of
gonococci. PilQ, a secretin class of proteins, is a vital outer membrane protein
composed of 12 subunits that can act as a porin and serve as a bridge to the
assembled pilus fibrils for them to be able to pass from the inside to the outside of
bacterial outer membrane. PilC proteins (PilC1 and PilC2) play a crucial role in
epithelial cell adherence of the bacteria. It is also located at the tip of the pili, which
suggests that it is the adhesion that binds gonococci to the host cells.

The gonococcus possesses a cell envelope composed of three distinct layers: an

inner cytoplasmic membrane, middle peptidoglycan cell wall, and an outer
membrane. The outer membrane is comprised of LOS, phospholipid, and variety of

proteins.
Porin (PROTEIN 1) is designated as protein 1 and is closely associated in the
membrane with LOS. It provides channels that allow aqueous solutes to pass through
the hydrophobic outer membrane. It is also believed that it plays a key role in
pathogenesis. Porin is the product of a gene called as porB. The two major antigenic
classes, PorB1A and PorB1B, is the basis for the most commonly used as gonococcal
typing systems. The strains that express PorB1A and PorB1B are associated with the
resistance of N. gonorrhea to the bactericidal effect of the normal human serum with
intensified tendency to cause bacteremia. This porin-related serum resistance is due
to the binding of serum to loops on the porin protein of the complementary
downregulatory component of Factor H or C4bp. PorB1A promotes invasion of
epithelial cells, which aids in justifying the tendency for the dissemination of the
bacteria.

***(PORIN
o for food
o protection from human normal serum and also protection from
oxidative burst
o Inhibition of phagolysosome

Opa (phase-variable opacity related) proteins are outer membrane proteins, with
molecular weights of 20 to 28 kDa, which increases the adhesion between the
gonococci and to epithelial cells. It is encoded by opa gene. It also facilitates the
entry of the bacteria into host cell and interactions with the immune system. Some
Opa variants appear to promote invasion of epithelial cells. The heparin-related
compounds and CD66 (Carcinoembryonic antigen-related cell adhesion molecules or
CEACAMs) are the two Opa receptors on the eukaryotic cells that Opa proteins can

bind to, resulting in downregulation of immune responses. The CEACAM binding

triggers neisserial engulfment and transcellular transcytosis through polarized
epithelia allowing the bacteria to enter into the subepithelial spaces. On the other
hand, HSPG binding allows effective neisserial uptake into the non-polarized
epithelial cells. HSPG encourages the passage of bacteria from the infected tissues
back to the mucosal surface.
***Opa (Protein 2)
o for adhesion
o intergonococcal adhesion
Reduction-modifiable protein, which is present in all gonococci in close
association with porin and LOS, can stimulate blocking antibodies that reduce
bactericidal activity of the serum after exposure to an infected partner.
***Reduction Modifiable Protein (Protein 3)
o responsible for ineffective Antibody production
Other outer membrane proteins that contribute to the virulence of the bacterial:
Multiple Iron-Repressible Proteins has specific receptors for human
transferrin and lactoferrin. The transferrin receptor is required for
successful urethral infection. The role of lactoferrin receptor has not yet
been discovered yet; it does not contribute to the infectivity of the
organism.
***IgA1 Proteases, present in the N. gonorrhea, protects them from
secretory IgA antibody at mucosal surfaces. It cleaves the heavy chain of
the human immunoglobulin at different points within the hinge region. It
is thought that the Fab fragments of IgA1 may bind to the bacterial cell
surface and block the Fc-mediated functions.
Gonococcal lipooligosaccharide (LOS) is composed of Lipid A and a core
oligosaccharide, which lacks O-antigen side chains. One interesting characteristic
that distinguish between neisserial LPS from enteric LPS is that neisserial LPS has
highly-branched basal oligosaccharide structure including the absence of repeating
O-antigen subunits. Therefore, Neisserial LPS is known as lipooligosaccharide
(LOS). LOS possesses endotoxic activity and contributes to ciliary loss and
exfoliation of mucosal cells. It may undergo high frequency phase and antigenic
variation, which may contribute to the pathogenesis of the infection as well as
resistance to bacterial anti-LOS antibodies in the normal serum.
***LOS
o For the stimulation of immune system
o Responsible for eliciting inflammatory response
The peptidoglycan layer of the N. gonorrhea contributes to the inflammatory
response through its lytic transglycosylases, which produce and release highly
inflammatory peptidoglycan monomers. These peptidoglycan monomers or
fragments are toxic. Gonococci produce a surface polyphosphate creating a
hydrophilic, negatively charged cell surface that encapsulates the bacteria.

III.

Mode of Transmission
The primary risk factor in acquiring gonorrhea is through sexual intercourse with
an infected partner. Gonorrhea and other STDs are usually transmitted by people
with in-apparent infection or asymptomatic infection or by those who have
symptoms that they ignore or discount. The risk of transmission from female infected
with N. gonorrhea to a male partner is only 20% per episode and it increases to as
much as 60% to 80% after four or more exposures compared to male-to-female
transmission with the approximate percentage of 50% to 70% per contact. Anal
transmission of N. gonorrhea is also efficient. Transmission by anal intercourse is
efficient but the risk per episode has not been quantified. Transmission by fellatio
occurs less readily especially from the oropharynx to the urethra and transmission via
cunnilingus in any direction is rare.
A mathematical model was devised to identify the core group and to target
members for case finding, treatment, and other prevention strategies. Demographical
and social characteristics that directly or indirectly affect or influence the frequency
of the disease include young age, low educational and social economic levels,
commercial sex, illicit drug use, and similar factors. Other factors include poorly
understood psychosocial determinants of partner selection, cultural factors that affect
the response of the symptoms, and reduced access to health care.
Rectal infection is acquired both receptive anal intercourse and perineal
contamination with cervicovaginal secretions.
Pharyngeal infection is acquired through receptive oral sex but probably rarely
through kissing. It is acquired efficiently by fellatio than by cunnilingus. It is also
asymptomatic.
Infection of the Male Urethra
It occurs in men as an acute urethritis, which is the result of the concomitant
inflammatory response towards the gonococci. The urethral discharge is the hallmark
of the disease, which is associated with polymorphonuclear leukocyte (PMN) or the
granulocytes influx and shedding of urethral epithelial cells. It has also been
demonstrated that progressive gonococcal infection has high concentrations of
chemokine interleukin (IL)-8, cytokines IL-6 and tumor necrosis factor- (TNF-)
elicited by LOS. This release of cytokines and chemokines trigger the PMN influx,
which initiate the inflammatory response associated with gonococcal urethritis. PMN
influx together with cytokine release creates a synergistic effect to the clinical
symptoms associated with the disease. The acquired immune response of humans to
gonorrhea is ineffective in slowing disease progression or even preventing it.
Gonococci are found within the PMNs and urethral epithelial cells.

Microscopic examination of urethral discharges shows that gonococci are found

within the PMNs. The interaction of gonococci with PMNs is dependent on the
presence of Opa proteins. Opa50 is the Opa protein class that recognizes host cells
heparin sulfate proteoglycans (HSPGs). Opa 52, on the other hand, is the Opa protein
class that recognizes members of the CEACAMs. Experimental infection of men
with Opa gonococci results in a shift to an Opa+ phenotype. An Opa+ phenotype is
also prevalent in clinical isolates obtained from men with naturally acquired
gonococcal infection. Primary male urethral epithelial cells do not express
CEACAMs, and an N. gonorrhoeae strain FA1090 Opa mutant is not impaired in its
ability to cause infection in a human experimental model would suggest that the role
of Opa proteins in gonococcal urethritis depends on their ability to initiate a
gonococcal-PMN interaction. Generating such inflammation may be adaptive for the
gonococcus. Opa-HSPG interaction is thought to trigger a signal transduction
cascade resulting in phosphatidylcholine-dependent phospholipase C-mediated
generation of diacylglycerol. Generation of diacylglycerol in turn activates acidic
spingomyelinase and results in ceramide production from spingomyelin. These
processes are speculated to modulate the cytoskeletal rearrangements required for
endocytosis of the cell-associated gonococcus.
CEACAMs serve as co-receptors for other cell surface receptors present in the
phagocytes. The engagement of CEACAM will send a priming signal within the
PMNs that will activate adhesion receptors without triggering a respiratory burst or
release of inflammatory mediators. Opa-CEACAM interaction plays a major role in
enhancing the survival of gononococci within the PMNs.
Porin contributes to the survival of gonococci intracellularly within the PMNs.
The gonococcal porin is unique from other gram-negative porins because it has the
ability to translocate to and insert into a targeted host cell membrane. Within the host
cell membrane, porin forms an anion selective, voltage gated channel that is
modulated with the presence of ATP or GTP. The insertion porin into the PMN
membrane inihibits degranulation by causing a change in membrane potential
without triggering respiratory burst within the PMN. Porins also have the ability to
inhibit phagosome maturation and downregulate cell surface receptors important to
immune function such as FcRII, FcRIII, and complement receptors 1 [CR1] and 3
[CR3]). Fc receptors bind to antibodies that are attached to infected cells to invading
pathogens.
Thus, Fc-, CEACAMs, HSPGs and integrin receptors present on the PMN cell
surface play role in gonococcal adherence and internalization.
Disease process
The urethral epithelial cell is the initial site for gonococcal infection in men. It is
a sequential process in which the initial interaction occurs when the gonococcal pilus
reaches the urethral epithelial cell. Intimate association of the urethral epithelium and

gonococcus is achieved through the interaction of asialyloglycoprotein receptor and

gonococcal LOS, which also results to the pedestal formation beneath the bacterium.
Endocytosis happens afterwards because of actin and clathrin-dependent processes.
ASGP-R mediated endocytosis results in endosomal fusion and acidification, which
results in clathrin-coat disassembly and uncoupling of the ASGP-R ligand complex.
After the gonococci are inside the epithelial cell, ASGP-R is recycled to the urethral
cell surface, where it is available to bind more gonococci. Only a small proportion of
gonococci use a macropinocytic mechanism to enter urethral cells and membrane
disorganization is not observed in this mechanism. The gonococcus also induces antiapoptotic events that prolong life of the epithelial cells.
The adherence of gonococcus to the ASGP-R is dependent on the presence of
galactose on the terminal lacto-N-neotetraose (LNnT) moiety on LOS of gonococcus.
The LNnT moiety imitates the human paragloboside and provides a means of escape
of the gonococcus to immune recognition. It can also serve as a sialic acid acceptor.
The presence of sialic acid on gonococcal LOS will mean an unstable resistance of
the bacteria to the bactericidal action of normal human serum. Gonococci bearing the
LNnT moiety exhibit enhanced infectivity on humans.
The sialylation of gonococcal LOS occurs inside the cell and it is mediated by
gonococcus-encoded sialyltransferase present in the gonococcal outer membrane.
The gonococci must parasitize cytosine 5-monophosphate N-acetylneuraminic acid
(CMP-NANA) to the human host because of its inability to synthesize this.
Sialylation of the LNnT epitope impairs the ability of gonococci to invade primary
urethral epithelial cells and epithelial cell lines, to cause disease in humans, and to be
phagocytized by neutrophils. Sialic acid removal by neuraminidase restores the
infectivity of gonococci within the lumen of the urethra in the absence of host
derived CMP-NANA. Neuraminidases produced by the vaginal microbiota may
remove sialic acid from sialylated gonococci. Cervical epithelia may also produce
neuraminidase. Neuraminidase and ASGP-R are also present on human sperm.
Sialylated gonococci when near to sperm cells may become desialylated through the
action of neuraminidase present in the sperm. Thus, subsequent gonococcal
adherence to the ASGP-R on sperm can facilitate disease transmission.
The intracellular fate of gonococci within the cervical epithelium is unclear.
Summary of the Infection of Male Urethra
A. Attachment and Interaction of the Bacterium and Gonococcus
1. Initial interaction occurs when the gonococcal pilus reaches the urethral
epithelial cell. Intimate association of epithelium and gonococcus is
achieved through the interaction of asialyloglycoprotein receptor and
galactose on the terminal lacto-N-neotetraose (LNnT) moiety on LOS of
gonococcus, which result to pedestal formation beneath the bacterium.

2. The interaction initiates a signaling cascade, which results in recruitment

of clathrin to the site of ASGP-R. The gonococcusASGP-R complexes
are internalized in clathrin-coated pits in an actin-dependent process.
B. Endocytosis of the Gonococcus
1.
processes.

Endocytosis happens afterwards because of actin and clathrin-dependent

2.
The enzyme, dynamin, cleaves the now-engulfed bacterium from the cell plasma
membrane. The bacterium now within an endosome.
3.
Within this endosome a drop in pH is proposed to release the ASGP-R from the
gonococcus surface and clathrin molecules also are released. The receptor-clathrin
complexes begin to disperse from the bacteria-containing endosome.
4.
After the gonococci are inside the epithelial cell, ASGP-R is recycled to the
urethral cell surface to bind more gonococci.
5.
Sialylated gonococci are eventually released from the urethral epithelium, where
they can then be transmitted to a female partner.

Infection of the Lower Female Genital Tract

In women gonococcus has the ability of the gonococcus to evade and subvert
host immune function. The cervical epithelium provides a source of alternative
pathway (AP) complement activity. C protein C3b is deposited on the lipid A portion
of gonococcal LOS and is rapidly inactivated to iC3b because of the affinity of
Cfactor H (fH) for sialylated LOS and for porin of PI.A isotype may augment C3b
inactivation.
CR3 serves as the primary receptor for N. gonorrhea adherence to and invasion
of the ectocervix and endocervix. Binding of gonococcal pilus to the I-domain of
CR3 probably allows the gonococcus to overcome electrostatic repulsion between its
own cell surface and that of the cervical cell. The twitching action of the gonococcal
pilus may act to juxtapose or place side by side the gonococcus and the cervical cell
surface where C concentration is optimal for the efficient opsonization for the
subsequent intimate adherence of iC3b on the organism surface and gonococcal porin
to the I-domain. The effective adherence of gonococcus requires the cooperative
action of iC3b bound to the gonococcal surface in conjunction with gonococcal porin
and pilus. The participation of CR3 results in a complex signaling cascade in which a
vinculin and ezrin enriched focal complex formation occurs before the membrane
ruffle formation. The ruffling is initiated by the signal transduction cascade that is
dependent upon the activation of wortmannin-sensitive kinases and RhoGTPases.
Gonococci are then internalized within macropinosomes.
Upon infection of cervical epithelia, gonococci release a phospholipid D
homologue that gains access to the cervical intracellular environment nonspecifically
through macropinocytosis of gonococci. N. gonococcal Phospholipase D (NgPLD)
promotes infection of the cervical epithelium because it augments signaling events
that trigger CR3 mobilization to the cervical cell surface and this ensures gonococcal
receptor availability and efficient targeting to and association with the cervical cell
surface. It also modulates cervical cell signal transduction events leading to
membrane ruffling.
It is the same with the invasion of male urethral epithelial cells that the
intracellular fate of the gonococci within the cervical epithelium is also unclear.
Gonococcal invasion in the absence of respiratory burst increases the number of
gonococci that survive intracellularly and the inactivation of the Csystem enhances
gonococcal survival extracellularly. Destabilization of host cell signal transduction
and the C system by the gonococcus within the lower female genital tract allows this
bacterium to obtain a carrier-like state.
Opa (or transparent) gonococci predominate in the fallopian tubes and in the
cervix at the time of menses. While, Opa + gonococci predominate in the male urethra
and the cervix at the time of ovulation.

Summary of the Infection of the Lower Female Genital Tract

A. Alternative Pathway Activation
1. Alternative pathway complement components are produced and released by the
cervical epithelia. On N. gonorrhoeae infection, complement is activated.
2. Gonococcal pilus binds to the I-domain (red region on CD11b) of CR3 receptor,
which comprises the integrins CD11b and CD14, allowing the bacterium to
overcome the electrostatic repulsion between its own cell surface and that of the
host cell.
3. As the pilus retracts, this places the gonococcus within proximity to the cervical
cell surface where complement components would be sufficient to allow
deposition upon the bacterial cell surface.
4. C3b forms a covalent association with amine groups on the deep core region of
gonococcal lipo-oligosaccharide (LOS) and is rapidly inactivated to iC3b.
5. The affinity of gonococcal porin for factor H may augment iC3b formation. The
proximity of porin to LOS in the outer membrane may spatially favor the
intimate association between iC3b and porin with the CR3 I-domain.
B. Internalization as Macropinosomes
1. Engagement of CR3 triggers a complex signal transduction cascade mediated by
the Src-family tyrosine kinases and Rho GTPases. These processes result in
vinculin- and ezrin-enriched focal complex formation and membrane ruffling,
that is, the trigger mechanism of invasion.
2. Secreted N. gonorrhoeae phospholipase D (NgPLD) modulates cervical cell
signal transduction by playing a role in CR3 recruitment to the cervical cell
surface and by modulating cytoskeletal reorganization. Additionally, this protein
augments intracellular survival of gonococci after their internalization within as
macropinosomes.
3. Sialylated gonococci are eventually released from the cervical cell, where they
are free to invade more of the cervical epithelia or where they become primed
for transmission to the male urethra on sialic acid removal by sialidases present
within the female genital tract.

Infection of the Upper Female Genital Tract

The infection of the upper female genital tract is caused by the ability of
gonococci to exhibit twitching motility in conjunction with hormonal changes which
influence the expression of C and molecules serving as gonococcal receptors within
the female genital tract. The expression of the lutropin receptor (LHr) increases from
the endometrium to the fallopian tubes, and expression is optimal during
menstruations. The LHr serves as a receptor for gonococcal invasion of fallopian
tube epithelia. Ribosomal protein L12 acts like a human chorionic gonadotropin
(hCG) that can compete with the interaction of gonococci and LHr receptors and it
also facilitates gonococcal transcytosis in fallopian tube epithelia. Due to the
presence of LHr in the placental membranes and decidua, it could result to severe
fetal complications and spontaneous abortion due to N. gonorrheae infection. LHrs
also induce the loss of ciliary action of the fallopian tube if the disease is left
untreated. The cytotoxicity of ciliated cells is attributed to the peptidoglycan layer
and LOS due to the production of inflammatory cytokine TNF(Tumor Necrosis
Factor). The effect of the loss of ciliated cells provides the gonococcus access to subepithelial cells.
IV.

Signs and Symptoms

The disease may become symptomatic or asymptomatic. For the

symptomatic infection, the most prevalent manifestation of gonorrhea in men is
acute urethritis. Urethral discharge and dysuria are the major symptoms. Initially,
the discharge may be scant and mucoid, but within 1 to 2 days it becomes
purulent or in other words it contains pus. Dysuria is usually more prominent, and
the discharge is generally more profuse and purulent. Cutaneous abscesses have
been described, typically involving the finger or the penile shaft, and probably
result from inoculation of preexisting lesions. The symptoms clearly depend in
part on the infecting organism. Por1A serovars and AHU- and related auxo-types

of N. gonorrhea are frequently associated with asymptomatic urethral infection.

For men with symptomatic infection:
A burning sensation when urinating;
A white, yellow, or green discharge from the penis
Painful or swollen testicles (although this is less common)
Cutaneous abscesses on the finger or penile shaft
In women, the symptoms develop within 10 days. The dominant
symptoms are increased vaginal discharge, dysuria, and intermenstrual bleeding
sometimes triggered by coitus (sexual intercourse). Abdominal pain or pelvic pain
indicate arising infection. Through physical examination, purulent or
mucopurulent cervical exudate and signs of mucopurulent cervicitis, such as

edema in a zone of cervical ectopy or endocervical bleeding induced by gentle

sex.
Rectal infection is acquired both receptive anal intercourse and perineal
contamination with cervicovaginal secretions. Rectal gonococcal infection is
usually asymptomatic but some patients have proctitis (inflammation of the
rectum and anus), anal pruritus, tenesmus (a continual or recurrent inclination to
evacuate the bowels), purulent discharge, or rectal bleeding.

Pharyngeal infection is acquired through receptive oral sex but probably

rarely through kissing. It is asymptomatic but rare cases may cause overt
pharyngitis with redness and purulent discharge. There are also observed acute
gingivitis, otherwise unexplained oral ulcerations, and intra-oral abscesses.
Gonococcal conjunctivitis may also be seen in people with genital
gonorrhea as a result of autoinoculation, but some cases it may be acquired
through orogenital exposure. Gonococcal conjunctivitis is usually painful, with
photophobia and copious, purulent exudate, corneal ulceration can supervene
rapidly without prompt antibiotic therapy. Gonococcal abscess involves the penile
shaft and it is also the first clinical representation of congenitally patent median
raphe duct of the penis. Ophthalmia neonatorum in infants, typically manifests as
purulent, edematous conjunctivitis.

***Most common:
Men
o Acute urethritis
o Dysuria

V.

Women
o Vaginal discharge
o Inflammation

Specific Laboratory Tests

All Neisseria spp. rapidly oxidize dimethyl-p-phenylenediamine and
tetramethyl-p-phenylenediamine, which is the basis for the oxidase test. The
different species of Neisseria are differentiated by their ability to grow on
selective media. The Neisseria spp. grow on media enriched with glucose, not
maltose, sucrose, or lactose and they also reduce nitrites. They have also the
inability to grow well at reduced temperatures and simple nutrient agars.
Gonococci do not tolerate drying thats why all the patient samples must
be inoculated immediately to appropriate growth or transport medium. The
optimal temperature for Neisseria is in between 35-37 degree Celsius. The growth
also requires approximately 5% of atmospheric carbon dioxide. They also have
the ability to grow aerobically but can also grow anaerobically if nitrites are
provided as electron acceptor. Colonies appear 24-48 hours after inoculation.
Neisseria spp. is also inhibited by many fatty acids and it is necessary to
incorporate starch or other substances capable of absorbing fatty acids. Chocolate
agar enriched with glucose is a satisfactory medium because the growth of
Neisseria requires vitamins, amino acids, and iron.
When Neisseria sample is isolated from the patients pharynx, rectum, or
cervix it has the tendency to contain high concentrations of normal microbiota.
The solution to this problem is use media containing antimicrobial agents, which
allow only the growth of Neisseria species inhibiting non-pathogenic Neisseria
and other species. There two available media for this purpose: chocolate agar that
contains vancomycin, colistin, nystatin, and trimethropin or also called the
Thayer-Martin Medium; and New York City Medium, a translucent selective
medium for Neisseria.
Collection of specimen

Men urethral secretion (in the morning or at least 1 hour after last
miction)
Acute urethritis: direct swab/loop collection (abundant secretion)
Chronic infection: loop, special swab inserted 2 cm into urethra and rotated.

Women endocervical secretion (during gynecology exam)

Insert valve

Use 2 consecutive swabs (1 for microscopy and 1 for inoculation of culture

media)
Insert each swab into cervix and rotate

Diagnosis
Isolation of N. gonorrhea is the traditional standard for diagnosis. Culture
is sensitive yet inexpensive way of diagnosing N. gonorrhea and it practically
preserves an isolate for antimicrobial susceptibility testing. It is also considered as
the only appropriate test in forensic settings. NAATs replaced culture considering
it to have a more convenient specimen management and their advantage in testing
urine and vaginal swabs. Non-amplified DNA probe tests still remain in use
although manifest lower sensitivity compared to culture and NAATs. Microscopy
of Gram-stain smears is a useful and effective in the diagnosis of symptomatic
urethritis in men.
A. Culture
Culture of N. gonorrhea is performed on a modified Thayer-Martin agar,
an antibiotic-containing selective medium. It has 95% sensitivity for urethral
specimens in man and has 80-90% sensitivity for endocervical infection in
woman. It is a selective medium used in qualitative procedures for the isolation
of Neisseria gonorrhoea with suppression of most other gram-negative diplococci,
gram-negative bacilli, gram-positive organisms, and yeast. It is a modified
chocolate agar by the addition of antimicrobics to suppress the growth of some
contaminating organisms but which allowed N. gonorrhoeae and N. meningitidis
to grow. Sterile clinical specimens such as blood, synovial fluid, and
cerebrospinal fluid must be inoculated onto enriched chocolate agar or another
non-selective medium and it does necessitate the use of antimicrobial agents
because these specimens are sterile and it does not contain the normal flora or
microbiota. It must also be inoculated in broth medium and tested by NAAT to
increase the sensitivity and increase efficiency.
B. Nucleic Acid Amplification Tests (NAATs)
1.
2.
3.
4.

Transcription-Mediated Amplification Test (Aptima)

Polymerase Chain Reaction (Amplicor)
XPERT Rapid PCR Test (Cepheid)
DNA Strand Displacement Assay (Probe Test)

NAATs are used in people with asymptomatic infection. It is not

significantly more sensitive but have specificities greater than 99% for N.
gonorrhea and it offers more advantage in specimen management because it
retains sensitivity when used in voided urine or self-collected vaginal swabs.

Transcription-Mediated Amplification Test

TMATs have positive predictive value of at least 95% in women.
Indicating false-positive result is a rare case even in low prevalence populations.
It is reliable for rectal and pharyngeal Neisseria gonorrheal infections.
C. Gram Stained Smears (GOLD STANDARD)
Gram stained smears are used in more than a century for clinical
specimens of N. gonorrhea. It utilizes methylene blue as dye. The microscopy of
Gram-stained smear is positive if it is Gram-negative diplococci with the
association of neutrophils. On the other hand the smear is negative if no such
organism is seen on the microscope. In men with symptomatic urethritis, it is at
least 95% sensitive and highly specific for the diagnosis of gonorrhea, however it
is not useful for other anatomic parts. Microscopy is insensitive and nonspecific
for detection of pharyngeal infection.
Positive test (+): Translucent Colonies in Thayer Martin Agar
D. Other Diagnostic Methods
1. Non-Amplified DNA Probe tests-These tests are less sensitive than
culture and NAATs and they are not useful for the detection of
gonococcal antigens.
2. Immunochemical Detection of Gonococcal Antigens
a. Enzyme Immunoassays with polyclonal anti-gonococcal
antibodies
b. Fluorescein-Conjugated Monoclonal Antibodies for direct
fluorescence microscopy
3. Cystine trypticase agar (CTA) Test-Neisseria species produce acid
from carbohydrates by oxidation producing yellow color.
4. Oxidase test-All Neisseria spp. rapidly oxidize dimethyl-pphenylenediamine and tetramethyl-p-phenylenediamine
5. Agglutination with Anti-sera
VI.

Period of Communicability
As long as the individual harbors the organism, he/she is infectious and may
extend to months if left untreated. However, effective treatment could end
susceptibility within hours.

VII.

Incubation Period
The incubation period is brief and genital symptoms often bring people to abrupt
treatment of the disease, thus the duration of gonorrhea is short, typically several days

for men and 2 weeks for women. There is a 50% efficiency of uncomplicated
gonorrhea through heterosexual intercourse especially in people with high rates of
partner change-an average of two partners within 1- or 2- week interval between
acquisition of infection and its resolution.

VIII.

Prognosis/Outcome of disease
Acute epididymitis is the most common complication of urethral gonorrhea.
Penile edema without other overt inflammatory signs (bull-headed clap) is
occasionally seen on either gonococcal or nongonococcal urethritis. Uncommon
complications include penile lymphangitis, periurethral abscess, acute prostatitis,
seminal vesiculitis, and lastly infections of Tysons and Cowpers glands. Urethral
strictures were also considered common consequences of gonococcal urethritis in the
pre-antibiotic era and might have primarily resulted from the treatment of caustic
solutions such as silver nitrate and potassium permanganate.
Pelvic Inflammatory Disease refers to a spectrum of upper genital tract infections
and may occur as symptomatic or asymptomatic. Symptomatic PID is manifested by:
Endometritis
Salpingitis
Tubo-ovarian abscess
Pelvic tonitis
Perihepatitis
Mucopurulent cervicitis
Most consistent symptom of PID is low abdominal pain. It often follows the
onset of menses by a few days. There is also a pelvic adnexal tenderness, uterine
fundal tenderness,and pain elicited on moving the cervix.
Infertility resulting from fallopian tube obstruction is the most common serious
consequence of PID.
Perihepatitis or Fitz-Hugh-Curtis syndrome, occurs due to the direct extension of
N. gonorrheae from the fallopian tube to the liver capsule and overlying peritoneum.
It may cause bacteremic dissemination and lymphangitic spread. It results to
abdominal pain, hepatic tenderness, and right upper quadrant peritoneal
inflammatory signs. Laparoscopy may show violet string adhesions between the
liver capsule and parietal peritoneum.
Disseminated Gonococcal Infection (DGI) results from the bacteremic
dissemination of N. gonorrhea. Septic arthritis and characteristic syndrome of
polyarthritis and dermatitis are the predominant manifestations. DGI also causes

infective arthritis in young adults. Gonococcal endocarditis was common during the
pre-antibiotic era.
Neonatal and Pediatric Infections
Gonococcal conjunctivitis (ophthalmia neonatorum) is the most common
clinically recognized complication of gonorrhea in infants. It is a common cause of
blindness in infants.
Systemic illness with septicemia and arthritis can also develop in neonates
exposed to gonorrhea. Rectal gonococcal infection is sometimes seen in neonates and
vaginal infection is uncommon because the vaginal mucosa of is well-estrogenized
by circulating maternal hormone.
Summary of Complications:
a. Gonorrhea in Men
i. Acute epididymitis
ii. Gonococcal prostitis (rare)
iii. Penile edema
iv. Periurethral abcess or fistula
v. Seminal vesiculitis
vi. Balanitis (For uncircumcised men)
b. Gonorrhea in Pregnant Women, Neonates, and Children
i. Salpingitis and Pelvic Inflammatory Disease (PID) which causes high rate
of fetal loss (highest during first trimester)
ii. For the infants:
1. Prolonged rupture of the membranes
2. Premature delivery
3. Chorioamnionitis
4. Funistis (infection of the umbilical cord stump)
5. Sepsis
iii. For the Neonates
1. Ophthalmia neonatorum (clinical manifestation begins 2-5 days
after birth)
2. Corneal ulceration
3. Blindness
c. Anorectal Gonorrhea
i. Acute proctitis
ii. Anorectal pain or pruritus
iii. Tenesmus
iv. Purulent rectal discharge
v. Rectal bleeding
d. Pharyngeal Gonorrhea
i. Cervical lymphadenitis
e. Ocular Gonorrhea in Adults
i. Swollen eyelid

ii. Severe hyperemia and chemosis

iii. Profuse purulent discharge
f. Gonococcal Arthritis
i. Bacteremic stage
1. High fever and chills
2. Painful joints with tenosynovitis with skin lesions (lesions are
usually on the extremities with number of 5 and 40)
ii. Joint-localized stage
1. Suppurative Arthritis
a. Involves one or two joints most often the knees, wrists,
ankles, and elbows (in decreasing order of frequency
Most common:
o Female
Salpingitis
PID (Pelvic inflammatory disease)
o Infants
Ophthalmia neonatorum
1% AgNO3
Needs penicillin for prevention
Adults:Ocular gonorrhea
o Disseminated Gonococcal prevention (Spread to other body parts)
o Arthritis- joints
o Men
Acute epididymitis=leads to sterility
IX.

Prophylaxis/Control Measures
a. Control Measures
Condoms
Spermicidal preparations
Screening for STIs
Individual patient counseling including behavior modification
Partner management
b. Treatment
Diagnosis Treatment of Choice
Uncomplicated gonococcal infection of the
cervix, urethra pharynx, or rectum
First line regimen

Ceftriaxone (250 mg IM, single dose)

Alternative regimen

Cefixime (400 mg PO, single dose)

or
Cefizoxime (500 mg IM, single dose)
or

Cefotaxime (500 mg IM, single dose)

or
Spectinomycin (2g IM, single dose)
or
Cefotetan (1g I, single dose) + probenecid (1g
PO, single dose)
or
Cefoxitin (2g IM, single dose) + probenecid
(1g PO, single dose)
Epididymitis
Pelvic Inflammatory Disease (PID)

Gonococcal conjunctivitis for adult

Ophthalmia neonatorum
Disseminated gonococcal Infections
Initial therapy
Patient tolerant of B-lactam drugs

Patient allergic to B-lactam drugs

Continuation therapy
Meningitis or endocarditis

PARENTERALS
Cefotetan (2g IV q12h) or Cefoxitin (2g IV
q6h) + Doxycycline (100 mg IV or PO q12h)
or
Clindamycin (900 mg IV q8h) + Gentamicin
(loading dose of 2mg/kg IV or IM, then
maintenance dose of 1.5mg/kg q8h)
OUTPATIENTS
Ceftriaxone (250 g IM once) + Doxycycline
(100 mg PO bid for 14 days) + Metronidazole
(500 mg PO bid for 14 days)
Ceftriaxone (1g IM, single dose)
Ceftriaxone (25-50 mg/kg IV, single dose not
to exceed 125 mg)
Ceftriaxone (1g IM or IV q24h; recommended)
or
Cefotaxime (1g IV q8h)
or
Ceftizoxime (1g IV q8h)
Spectinomycin (2g IM q12h)
Cefixime (400 mg PO bid)
*Hospitalization is indicated to
suspected meningitis or endocarditis

Drug of Choice:
Ampicillin
Ceftriaxone
Penicillin resistant: Fluoroquinolones
Pregnant women: Azithromycin

exclude

X.

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