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GONORRHEA (PATHOGEN (treatment (treatment in adults (Due to emerging…

- - - - vaginal sex
      - childbirth
      - oral sex
      - Anal sex
  - - - The bacterium that causes gonorrhea infects the female reproductive tract by breaking connections between cells in the tract's protective lining, according to new research published in PLOS Pathogens.
        
        Usually, infected cells in the lining can be shed and disposed of without breaking the tight connections between cells that keep the lining uncompromised. N. gonorrhoeae appears to be able to break these connections and induce cell shedding, opening paths for penetration without reducing its ability to adhere to and invade the cells of the lining.
        
        It causes distruptions by promoting activation and accumulation of a human protein known as non-muscle myosin II. Depending on the particular genes being expressed by N. gonorrhoeae at any given time, it can either promote or inhibit this penetration mechanism.
        
        In women, the opening of the uterus, known as the endocervix, serves as a primary infection site for N. gonorrhoeae.
    - - Attaches itself to the cells and the tissues using a rod shaped protein structure called Type IV pili that recognizes a molecule of the host and bind to it
      - Type IV pili is essential for virulence in N. gonorrhoeae because it mediates specific attachment to human mucosal cells, initiating the infectious process
  - - - Gonorrhea is a very common infectious disease. It is the second most prevalent sexually acquired infection in the United States, with more than 300,000 reported cases per year. The Center for Disease Control and Prevention (CDC) estimates that annually more than 700,000 people in the United States get new gonorrhea infections
      - Approximately 75 percent of all reported cases of gonorrhea are found in younger persons 15 to 29 years of age
    - - The prevalence of sexually transmitted diseases was determined among 370 prostitutes in Kuala Lumpur, Malaysia. Gonorrhoea cases (14.25%) and was associated more often with pelvic inflammatory disease.
  - - - pain or feel a burning sensation during urination.
      - inflammation of the foreskin.
      - an unusual discharge from the tip of the penis which may be white, yellow or green.
      - pain or tenderness in testicles (less common)
    - - an unusual vaginal discharge. which may be thin or watery and green or yellow in color.
      - pain or tenderness in the lower abdominal area (less common)
      - pain or feel a burning sensation during urination
      - bleeding when period, heavier period and bleeding after sex (less common)
  - - - empirical therapy using first-line recommendations
        
        highly effective
        
        widely available.
        
        affordable in appropriate quality and dose
        
        lack toxicity
        
        cure >95% of infected patients
    - - Due to emerging strains of drug-resistant Neisseria gonorrhoeae, the Centers for Disease Control and Prevention recommends that uncomplicated gonorrhea be treated only with the antibiotic ceftriaxone in combination with either azithromycin (Zithromax, Zmax) or doxycycline (Monodox, Vibramycin, others)
        
        ceftriaxone - given by injection to the patients
        
        azithromycin or doxycycline - taken orally.
      - treated with antibiotics
      - Oral gemifloxacin (Factive) or injectable gentamicin, combined with oral azithromycin, is highly successful in treating gonorrhea.
        
        this treatment is for treating people who are allergic to cephalosporin antibiotics, such as ceftriaxone.
    - - dual antimicrobial therapy. both antibiotics should be administered together on the same day.
        
        ceftriaxone
        
        a single-intramuscular (IM) injection of 250 mg provides sustained and high bactericidal levels in the blood
        
        clinical experience indicates that ceftriaxone is safe and effective for the treatment of uncomplicated gonorrhea at all anatomic sites, curing more than 98% of all infections
        
        azithromycin (second antimicrobial)
        
        preferred to doxycycline because of the convenience and adherence advantages of single-dose therapy
        
        the substantially higher prevalence of gonococcal resistance to tetracycline than to azithromycin
        
        Recent clinical trials showed that dual treatment with a single 320-mg dose of oral gemifloxacin plus a 2-g dose of oral azithromycin, or dual treatment with a single 240-mg dose of IM gentamicin plus a 2-g dose of oral azithromycin, were effective for uncomplicated urogenital gonorrhea
        
        when ceftriaxone is contraindicated (a specific situation in which a drug, procedure, or surgery should not be used because it may be harmful to the person)
- - - - It has evolved, acquired and developed nearly all known physiological mechanism of AMR e.g. (i) antimicrobial destruction or modification by enzymatic means, (ii) target modifications or protections that reduces affinity for the antimicrobials, (iii) decreased influx of antimicrobials and (iv) increased efflux and antimicrobials
      - The bacteria developed AMR through horizontal gene transfer (transformation and subsequent recombination into the genome by chromosomal or plasmid DNA) or conjugal transfer of plasmid AMR gene.
      - N. gonorrhoeae has an extraordinary capacity to alter its genetic material because it is naturally competent for transformation and effectively change its genome through all types of mutation.
      - Exposure to antimicrobials for treatment of gonorrhea or other infections promotes selection of resistant strains and coexisting of commensal species e.g. in the pharynx also promotes gene transfer.
      - E.g. Sulfonamide resistance in N. gonorrhoeae overcame by over-synthesis of p-aminobenzoic acid or by alterations of folP gene encoding the drug target enzyme (bacterial dihydropteroate synthase) thus reducing sulfonamide bacteriostatic activity
      - Reference
      - Drug-Resistant Gonorrhea
    - - PorB targets the inner mitochondrial membrane of host cell to directly trigger the loss of membrane potential regulated by ATP binding
      - This PorB is present at the bacterial outer membrane and when ingested by the host immune cell, some PorB will be transported via outer membrane vesicles (OMV) to reach the host mitochondria
        
        This is proven by when the OMV in cytosol of host immune cell lack the surrounding host membrane because when in the cytosol already, the bacteria secretes the OMV without passing through any membrane
        
        Therefore, the OMV may target the PorB directly to the host immune cell mitochondria. The OMV were observed to be in close proximity to the mitochondria.
        
        The membranes of both the OMV and mitochondria were stained PorB positive
        
        N. gonorrhoeae is able to deliver PorB to host cells in the absence of bacterial attachment and suggests that this depend on OMV biogenesis. OMV biogenesis depends on the interaction of the outer membrane with the underlying peptidoglycan. Gene responsible is NGFG_01788
      - Macrophages, neutrophils and monocytes of the immune system fail to control N. gonorrhoeae replication because it modulates the antimicrobial activity including immune cell apoptosis pathway
        
        In uninfected host immune cells, cytochrome c was found in the mitochondria containing fractions but not in the cytosol. When cytochrome c is released into the cytosol, this triggers apoptosis.
        
        Caspase 3 activation causes membrane blebbing, a characteristic of apoptotic cell death. Cytosolic cytochrome c causes the proteolytic cleavage and activation of cell death executioner caspases (caspases 3 and 7).
        
        OMV exposure = translocation of PorB to mitochondria. To check apoptosis, need to determine mitochondrial health. This exposure causes the cytochrome c from mitochondria released to cytosol and triggers the activation of caspase 3.
        
        This is proven by real time imaging where PBS treated macrophages remained viable over 48 hours of imaging every 30 minutes but OMV treated macrophages lost the TMRM (fluorescence dye) signal after 10 hours.
      - Reference
      - Live imaging for OMV inducing apoptosis
  - - - Possible vaccines to be developed
    - - N.gonorrhoeae suppresses the development of Th1- and Th2- driven adptive immune responses
        
        Resistant to phagocytic killing
      - Eliciting Th17- driven innate defenses (such as anti-microbial proteins and phagocytes) that it appears to be capable of surviving
  - - - Enzyme-Linked Immunosorbent Assay (ELISA)
      - Indirect Haemagglutination reaction (IHA)
      - Gonococcal Complement-Fixation Test (GCFT)
    - - Sample taken from cervix, urethra, pharynx
    - - For sexually active women and men that are at high risk of STD
      - For man that has sex with men
      - Women that are pregnant or considering pregnancy
- - - - Multi-antigen sequence typing is a sequence-based method examining the diversity in two outer-membrane proteins
      - PCR detection of gonococcal-specific DNA
        
        The presence of N. gonorrhoeae specific DNA was determined using two in-house PCR methods targeting the ompIII and cppB genes using the DNA extract from the culture and the extracts from the underpants
      - Molecular typing using the sequence-based method NG-MAST
    - - Neisseria gonorrhoeae susceptibility to extended spectrum cephalosporins is decreasing and treatment failures are spreading, but no new drug class is licensed to replace them for immediate treatment.
      - Nucleic acid amplification tests are increasingly used to diagnose gonorrhoea but current commercially available tests do not detect antimicrobial resistance
      - Tests for gonorrhoea that allow individually tailored antimicrobial therapy at the first contact with health services will need to be point-of-care tests that can be integrated into the diagnostic process to give accurate results in around an hour.
      - Development of nucleic acid amplification tests that incorporate rapid detection of N. gonorrhoeae and its resistance determinants and ensuring the rational use of antimicrobials are priorities for controlling both gonorrhoea and antimicrobial resistance