School of Pharmaceutical Sciences
Section: Y2931
Student Name : Munyaradzi Amon Bishi
Registration : 11917503
Supervisor : Ms Palwinder Kaur
BP706PS: Capstone Project work
Topic : trying to find out if its possible or
more effective to treat gonorrhea
topically/Suppository form as opposed
to the oral dosage(tablet ) form of
treatment and finding out if it is more
effective .
II
References
1. Springer C, Salen P. Gonorrhea. [Updated 2022 Apr 21]. In: StatPearls [Internet]. Treasure
Island (FL): StatPearls Publishing; 2022 Jan-. Available from:
https://www.ncbi.nlm.nih.gov/books/NBK558903/
2.Hill SA, Masters TL, Wachter J. Gonorrhea - an evolving disease of the new millennium.
Microb Cell. 2016 Sep 5;3(9):371-389. doi: 10.15698/mic2016.09.524. PMID: 28357376;
PMCID: PMC5354566.
3.Green LR, Cole J, Parga EFD, Shaw JG. Neisseria gonorrhoeae physiology and pathogenesis.
Adv Microb Physiol. 2022;80:35-83. doi: 10.1016/bs.ampbs.2022.01.002. Epub 2022 Feb 18.
PMID: 35489793.
4.Unemo M, Seifert HS, Hook EW 3rd, Hawkes S, Ndowa F, Dillon JR. Gonorrhoea. Nat Rev
Dis Primers. 2019 Nov 21;5(1):79. doi: 10.1038/s41572-019-0128-6. PMID: 31754194.
Johnson AP. The pathogenesis of gonorrhoea. J Infect. 1981 Dec;3(4):299-308. doi:
10.1016/s0163-4453(81)91825-9. PMID: 6821096.
Introduction
Gonorrhea is a sexually transmitted infection/disease caused by the bacterium Nisseria gonorrhea .
Neisseria gonorrhoeae (the gonococcus) is a Gram-negative diplococcus, an obligate human pathogen,
and the etiologic agent of the sexually transmitted disease, gonorrhea[1]. Gonorrhea morbidity has risen
over the last 20 years secondary to the progression of antimicrobial resistance [1].
Recently, there has been a surge in gonorrhoea cases that has been exacerbated by the rapid rise in
gonococcal multidrug resistance to all useful antimicrobials resulting in this organism becoming a
significant public health burden[3].
Like other sexually transmitted infections , gonorrhea disproportionately impacts young adult populations
[1]. The bacterium Neisseria gonorrhoeae causes the sexually transmitted infection (STI) gonorrhoea,
which has an estimated global annual incidence of 86.9 million adults[4]. Gonorrhoea can be present as
urethritis in men, cervicitis or urethritis in women, and in extragenital sites (pharynx, rectum, conjunctiva
and, rarely, systemically) in both sexes[4] .
In most cases it also affects infants after birth from the infected mother ,thus leading to infections around
eyes often leading to permanent damage to the eyes of the infant .
As no gonococcal vaccine is available, prevention relies on promoting safe sexual behaviours and
reducing STI-associated stigma, which hinders timely diagnosis and treatment thereby increasing
transmission[4]. In addition, babies born to mothers harbouring gonococci in their genital tract may
become infected duringpassage down the birth canal and may develop gonococcal conjunctivitis and/or
show evidence of oro- gastric infection
Etiology of Gonorrhea
The obligate pathogen N. gonorrhoeae infects only humans in nature and most commonly
manifests as urethritis in men and cervicitis in women.Obligate pathogens refer to bacteria that
must manifest disease to facilitate transmission from one host to another [1]. The bacterium can
only survive in an infected host and cannot survive outside of the infected host [2] .
Undiagnosed and/or untreated gonorrheal urogenital infections can ascend through the upper
urogenital tract and cause many severe reproductive complications, most commonly but not
exclusively in women, such as endometritis, pelvic inflammatory disease, infertility, and/or lifethreatening morbidity via ectopic pregnancy [1].
The disease is characterized mainly by inflammation of mucus membrane of genitalia tract and
urethra.
If found in the lower reproductive tract of women , it can lead to serious, long-term
consequences of these infections which may ascend into the fallopian tube.
The damage caused by gonorrheal infection and the subsequent inflammatory response produces
the condition known as a pelvic inflammatory disease.
Additionally, the result of infection can produce new adhesions between internal tissues, which
can tear and reform, producing chronic pelvic pain.
Pathogenesis
N. gonorrhoeae infection starts with the adhesion of gonococci to epithelial cells, followed by
local cellular invasion. Gonorrhea has multiple surface proteins that facilitate adhesion. N.
gonorrhoeae utilize pili to initiate adhesion to epithelial cells [1]. Upon arrival into a new host,
micro-colony formation commences on non-ciliated columnar epithelial cells approximately 1 to
2 hours post-infection [2]. Once the micro-colonies achieve a cell density of approximately
100+, cellular rearrangement and host protein aggregation occurs, which leads to pilus-mediated
attachment of the gonococcus to the CD46 host cell-surface receptor [2].
Hair-like appendages, pili , cover the bacterial surface. Their ability to lengthen and retract
allows the bacteria to attach from a distance and move closer to the epithelial cells, promoting
cellular invasion [1].
Once bound, the pili structures on some of the bacteria retract through PilE depolymerization ,
which promotes tighter contact with the host cells through Opa binding to the CEACAM
(carcinoembryonic-antigen-related cell-adhesion molecules ) receptors. Upon CEACAM
binding, actin polymerization and rearrangement is induced within the host cell which results in
bacterial engulfment, transcellular transcytosis and release of the bacteria into the subepithelial
layer[2].
Other surface proteins involved in cellular attachment include Opa, opacity-associated
proteins.The coordinated expression of pili and Opa varies considerably . Organisms isolated
from the male urethra generally co-express pili and one of several Opa proteins .
However, in women, Opa expression varies depending upon the stage of the menstrual cycle and
whether or not the patient is taking oral contraceptives .
At mid-cycle, bacteria isolated from the cervix express Opa, whereas those isolated during
menstruation tend to be Opa negative .
Moreover, organisms isolated from infected fallopian tubes are almost universally Opa negative,
even though Opa expressing organism can be isolated from the cervix of the same patient.
Consequently, non-Opa expressing cells may be selected due to the extreme sensitivity of Opa
proteins to trypsin-like enzymes.
However, with the recent studies demonstrating Opa interactions with CEACAM receptors, it
has been observed that fallopian epithelial tube cell cultures do not appear to express CEACAM
receptors. Nonetheless, in the absence of these receptors, gonococci were found to still adhere
and invade. Consequently, CEACAM expression, or the lack of it, possibly allows for in
vivo phenotypic selection of distinct gonococcal bacteria on various tissues. All in all, Opa
expression does appear to increase gonococcal activity within the female genital tract .
Generally, Opa expression is absent in most re-isolates from female infections[2].
Inflammation
The other observed symptom of a gonorrheal infection is a massive recruitment of neutrophils to
the site of infection leading to the formation of a pustular discharge. Initially, Opa protein
expression was suspected to be intimately involved in PMN stimulation . Subsequently, it was
shown that following attachment of gonococci to the mucosa, the pro-inflammatory cytokines
IL-6 and TNF-alpha as well as the chemokine IL-8 are released leading to the recruitment of
neutrophils.
In addition, upon arrival at the sub-epithelial layer, gonococci release lipooligosaccharide, LOS
,which also attach to sperm cells and likely leads to transmission from males to uninfected sexual
partners. LOS and lipoproteins which further stimulate cytokine production as these outer
membrane components are detected by Toll-like receptors (TLRs) on immune cells . Host cells
also respond to bacterial peptidoglycan fragments within outer membrane vesicles via
cytoplasmic NOD-like receptors (NLRs) which also contribute to the secretion of additional proinflammatory cytokines[2] .
Despite the active recruitment of PMNs to a site of infection, gonococci can survive the
oxidative and non-oxidative defense mechanisms . Survival appears to correlate with gonococci
selectively triggering Th17-dependent host defense mechanisms by modulating expression of IL17 . Gonococci also must combat considerable oxidative stress by elaborating a number of
different enzymes during the inflammatory response in order to detoxify superoxide anions ,
hydrogen peroxide (H2O2), and hydroxyl radicals .
Gonococci must remove H2O2 because in the presence of ferrous ions the Fenton reaction is
initiated , which yields additional hydroxyl radicals . Catalase is used by the gonococcus to
eliminate H2O2 (which significantly increases the organism’s ability to resist in vitro neutrophil
killing) in conjunction with a periplasmic cytochrome c peroxidase .
Normally, superoxide ions are removed by superoxide dismutase enzymes (SOD) which convert
superoxide to H2O2 and water. However, the majority of N. gonorrhoeae strains have no
measurable SOD activity , suggesting that oxidants may be removed via an alternative
mechanism. The N. gonorrhoeae then utilizes manganese ions to counter the reactive oxygen
species accumulation. Manganese accumulates within the cell through the Mn uptake system
(MntABC), with Mn(II) and Mn(III) both taking superoxide and hydrogen peroxide molecules
non-enzymatically. Furthermore, Mn(II)-pyrophosphate and Mn(III)-polyphosphate complexes
are also effective in eliminating hydroxyl radicals that are formed via the Fenton reaction[2].
Current Treatments
The current treatments for Gonorrhea mostly range from oral to intravenous or intramuscular
treatments in both males and females . These are mainly for Genital and Urethral infections.
These treatments include the intravenous/intramuscular dose of 500mg ceftriaxone with
doxycline 100mg of which it is two times daily for 7 days .
The alternative or frontline of Gonorrhea is the single dose of cefixime 800 mg plus
azithromycin 1 g [1].
In patients who have an azithromycin allergy or who immediately vomit the drug, doxycycline
100 mg orally twice a day for 7 days is an alternative to azithromycin as a second
antimicrobial[1].