Transcript #10 Gram Negative Cocci: The Neisseria

Gram Negative Cocci:
the Neisseria
Introduction
 The family Neisseriaceae comprises the genera
- Neisseria
- Moraxella
- Kingella
- Eikenella.
 Neisseria gonorrhea and Neisseria meningitidis
are the most significant human pathogens.
General Characteristics of
Neisseria spp.
 Aerobic, Gram-negative cocci, 0.6 to 1.0 um in
diameter, often arranged in pairs (diplococci)
with adjacent sides flattened (like coffee
beans)
 Neisseria meningitidis is encapsulated whereas
Neisseria gonorrhea is not
 Oxidase positive
 Most catalase positive
 Nonmotile
 Acid from oxidation of carbohydrates, not from
fermentation
 Neisseria gonorrhea infections have a high
prevalence and low mortality whereas Neisseria
meningitidis infections have a low prevalence and
high mortality.
 Other species normally colonize mucosal surfaces
of oropharynx and nasopharynx and occasionally
anogenital mucosal membranes
 They have pili and an outer membrane with highly
branched basal oligosaccharides but no repeating
O- antigen subunits.
 They release outer membrane fragments (blebs)
during growth which contain LOS and may have a
role in pathogenesis.
 Both of Neisseria gonorrhea and Neisseria
meningitidis produce IgA1 protease.
Neisseria Associated Diseases
(ophthalmia neonatorum)
Neisseria gonorrhea
 The gonococcus is an obligate human pathogen.
 They attach to mucosal cells via pili and a protein
present in the outer membrane(Opa or protein II).
 Gonococci attach only to microvilli of nonciliated
columnar epithelial cells, attachment to ciliated
cells is not observed.
 Endocytosis follows attachment.
 Gonococcal infections are acquired by sexual
contact and usually affect mucous membranes of
the urethra in men and the endocrvix in women.
 Individuals with inherited complement deficiencies
have a markedly increased risk of developing
systemic infection by Neisseria and are subject to
recurring episodes of systemic gonococcal and
meningococcal infections .
Pathogenesis of Neisseria
gonorrhoeae
 Fimbriated cells attach to intact mucus
membrane epithelium
 Capacity to invade intact mucus membranes
or skin with abrasions
• Adherence to mucosal epithelium
• Penetration into and multiplication before passing
through mucosal epithelial cells
• Establish infection in the sub-epithelial layer
 Most common sites of inoculation:
• Cervix (cervicitis) or vagina in the female
• Urethra (urethritis) or penis in the male
Gonococcal Virulence Factors
 Antiphagocytic capsule-like negative surface charge
 Only fimbriated (piliated) cells (formerly known as colony
types T1 & T2) are virulent
 Outer membrane proteins (formerly Proteins I, II, & III)
•Por (porin protein) prevents phagolysosome fusion
following phagocytosis and thereby promotes intracellular
survival
•Opa (opacity protein) mediates firm attachment to epithelial
cells and subsequent invasion into cells
•Rmp (reduction-modifiable protein) protects other surface
antigens from bactericidal antibodies (Por protein, LOS)
 Acquisition of iron mediated through Tbp 1 and Tbp 2
(transferrin-binding proteins), Lbp (lactoferrin binding
protein) & Hbp (hemoglobin-binding protein)
Gonococcal Virulence Factors
(cont.)
 Llipooligosaccharide (LOS) (Lipid A plus core
polysaccharide but no O-somatic antigen
polysaccharide side chain) has endotoxin
activity
 IgA1 protease
 Acquisition in last two decades of two types of
antibiotic resistance:
• Plasmid-encoded beta-lactamase production
• Chromosomally-mediated changes in cellular
permeability inhibit entry of penicillins, tetracycline,
erythromycin, aminoglycosides
Clinical Manifestations
 Gonorrheal infection is generally limited to superficial
mucosal surfaces lined with columnar epithelium.
 The areas most frequently involved are the cervix, urethra,
rectum, pharynx and conjunctiva.
 Squamous epithelium (adult vagina) is not susceptible
(gonorrhea in young girls may present as vulvovaginitis).
 Mucosal infections are usually characterized by a marked
local neutrophilic response (purulent discharge)
 The most common symptom of uncomplicated
gonorrhea is a discharge that may range from a
scanty, clear or cloudy fluid to one that is copious
and purulent. Dysuria is often present.
 Endocervical infection is the most common form of
uncomplicated gonorrhea in women manifesting
as vaginal discharge and dysuria. About 50% of
those women are asymptomatic
 Rectal infection occurs in about one third of women with
cervical infection resulting form autoinoculation with
cervical discharge and are rarely symptomatic.
 Rectal infection in homosexual men is commonly
symptomatic.
 Pharyngeal infection in men or women may be a focal
source of gonococcemia.
 Ocular infection can have serious consequences (corneal
scarring or perforation)
 Disseminated infection result from gonococcal bacteremia.
 The most common form of disseminated gonococcal
infection is the dermatitis –arthritis syndrome.
 It is characterized by fever, chills, skin lesions (macular,
pustular, necrotic or hemorrhagic) and arthralgia (hands,
feet, elbow) due to periarticular inflammation of the tendon
sheaths.
 Occasionally a patient develops a septic joint with effusion.
 Rarely endocarditis or meningitis develop.
 Gonococci may ascend from the endocervical
canal through the endometrium to the Fallopian
tubes and ultimately to the pelvic peritoneum
resulting in endometiritis, salpingitis and finally
peritonitis.
 Women usually present with pelvic and abdominal
pain, fever, chills and cervical motion tenderness.
This complex of signs and symptoms is referred to
as pelvic inflammatory disease (PID).
 Complications of PID include tubo - ovarian
abscess, pelvic peritonitis or Fitz – Hugh and
Curtis syndrome (inflammation of Glisson's
capsule of the liver).
 As many as 15% of woman with uncomplicated
cervical infection may develop PID which may
have serious consequences including an
increased probability of infertility and ectopic
pregnancy.
Epidemiology of Gonorrhea
 Seriously underreported sexually-transmitted disease
 350,000 reported cases in USA in 1998
 Down from 700,00 cases in 1990
 Found only in humans with strikingly different
epidemiological presentations for females and males
 Asymptomatic carriage is major reservoir
 Transmission primarily by sexual contact
 Lack of protective immunity and therefore reinfection,
partly due to antigenic diversity of strains
 Higher risk of disseminated disease in patients with late
complement deficiencies
Epidemiology
 A very common infectious disease (2 unreported
cases for each reported case).
 Highest rates are a among women 15-19 years
and men 20-24 years of age.
 Gonorrhea is usually contracted from a sex
partner who is either asymptomatic or has only
minimal symptoms.
 It is estimated that the efficiency of transmission
after one exposure is about 35% from an infected
woman to an uninfected man and 50-60% from an
infected man to an uninfected woman.
 More than 90% of men with urethral gonorrhea
will develop symptoms within days, fewer than
50% of woman will do so.
Differences Between Men &
Women with Gonorrhea
IN MEN:
 Urethritis; Epididymitis
 Most infections among men are acute and
symptomatic with purulent discharge &
dysuria after 2-5 day incubation period
 Male host seeks treatment early preventing
serious sequelae, but not soon enough to
prevent transmission to other sex partners
 The two bacterial agents primarily responsible
for urethritis among men are N. gonorrhea
and Chlamydia trachomatis
Differences Between Men &
Women with Gonorrhea (cont.)
IN WOMEN:
 Cervicitis; Vaginitis; Pelvic Inflammatory
Disease (PID); Disseminated Gonococcal
Infection (DGI)
 Women often asymptomatic or have atypical
indications (subtle, unrecognized S/S); Often
untreated until PID complications develop
 Pelvic Inflammatory Disease (PID)
• May also be asymptomatic, but difficult
diagnosis accounts for many false negatives
• Can cause scarring of fallopian tubes leading to
infertility or ectopic pregnancy
Differences Between Men &
Women with Gonorrhea (cont.)
IN WOMEN (cont.) :
 Disseminated Gonococcal Infection (DGI):
•
•
•
•
•
•
•
•
Result of gonococcal bacteremia
Often skin lesions
Petechiae (small, purplish, hemorrhagic spots)
Pustules on extremities
Arthralgias (pain in joints)
Tenosynovitis (inflammation of tendon sheath)
Septic arthritis
Occasional complications: Hepatitis; Rarely
endocarditis or meningitis
Prevention & Treatment
 Penicillin no longer drug of choice due to:
• Continuing rise in the MIC
• Plasmid-encoded beta- lactamase production
• Chromosomally-mediated resistance
 Uncomplicated infection: ceftriaxone, cefixime or
fluoroquinolone
 Combined with doxycycline or azithromycin for
dual infections with Chlamydia
 Chemoprophylaxis of newborns against
ophthalmia neonatorum with 1% silver nitrate, 1%
tetracycline, or 0.5% erythromycin eye ointments
 Treatment of newborns with opthalmia neonatorum
with ceftriaxone
 Measures to limit epidemic include education,
aggressive detection, and follow-up screening of
sexual partners, use of condoms or spermicides
with nonoxynol 9
General Overview of Neisseria
meningitidis
 Encapsulated small, gram-negative diplococci
 Second most common cause (behind S.
pneumoniae) of community-acquired meningitis in
previously healthy adults; swift progression from
good health to life-threatening disease
 Pathogenicity:
• Pili -mediated, receptor-specific colonization of
nonciliated cells of nasopharynx
• Antiphagocytic polysaccharide capsule allows
systemic spread in absence of specific immunity
• Toxic effects mediated by hyperproduction of
lipooligosaccharide
Neisseria Meningitidis
 Meningococcal capsular polysaccharide provide
the basis for grouping these organisms.
 Thirteen serogroups have been identified
(A,B,C,H, I, J, K, L, 29 E, X, Z, Y and W135).
 Serogroups A, B, C, Y, and W135 account for
about 90% of all infections
 A few serotypes are associated with most cases of
meningococcal disease whereas other serotypes
rarely caused disease.
Diseases Associated with
Neisseria meningitidis
Following dissemination of virulent
organisms from the nasopharynx:
 Meningitis
 Septicemia (meningococcemia) with or
without meningitis
 Meningoencephalitis
 Pneumonia
 Arthritis
 Urethritis
 The human nasopharnx is the only known reservoir of
N.meningitidis.
 Meningococci are spread via respiratory droplets and
transmission requires aspiration of infective particles.
 They attach to the nonciliated columnar epithelial cells
of the nasopharnx via pili and outer membrane
proteins.
 They reach the blood stream and the events after
blood stream invasion are unclear.
 The integrity of the pharyngeal and respiratory
epithelium may be important in protection from
invasive disease.
 The presence of serum bactericidal IgG and IgM is
probably the most important host factor in
preventing invasive disease.
 Persons with complement deficiencies (C5, C6,
C7 or C8) may develop meningococcemia despite
protective antibody (6000 fold increase of risk).
Pathogenesis of Meningococcal
Disease
Specific receptors (GD1 ganglioside) for bacterial fimbriae on
nonciliated columnar epithelial cells in nasopharynx of host
Organisms are internalized into phagocytic vacuoles,
avoid intracellular killing in absence of humoral immunity
and complement system (patients with late complement
deficiencies are particularly at risk)
Replicate intracellularly and migrate to subepithelial
space where excess membrane fragments are released
Hyperproduction of endotoxin (lipid A of LOS) and
blebbing into surrounding environment (e.g., subepithelial
spaces, bloodstream) mediates most clinical manifestations
including diffuse vascular damage (e.g., endothelial damage,
vasculitis (inflammation of vessel walls), thrombosis (clotting),
disseminated intravascular coagulation (DIC)
Skin Lesions of Meningococcemia
NOTE:
Petechiae
have
coalesced
into
hemorrhagic
bullae.
Immunogenicity of Neisseria
meningitidis
 Following colonization of the nasopharynx,
protective humoral immunity develops against
the same or closely related organisms of the
same serogroup, but not against other
serogroups
 Bactericidal activity of the complement system
is required for clearance of the organisms
 Cross-reactive protective immunity acquired
with colonization by closely related antigenic
strains and with normal flora of other genera
(e.g., E. coli K1); progressive disease can occur
in absence of serogroup-specific immunity
Clinical Manifestations
 N. meningitides infection usually results from the blood
borne dissemination (meningococcemia) usually following
an asymptomatic or mildly symptomatic nasopharyngeal
carrier state or a mild rhinopharyngitis.
 The mildest form is a transient bacteremic illness
characterized by fever and malaise that resolves in 1-2
days.
 Acute meningococcemia is more serious and is often
complicated by meningitis.
 The manifestations of meningococcal meningitis are
similar to acute bacterial meningitis caused by organisms
such as S. pneumoniae, H. influenzae and E. coli.
 Manifestations result from both infection and increased
intracranial pressure.
 Chills , fever , malaise and headache are the usual
manifestations of infection.
 Headache, photophobia, vomiting and rarely papilledema
may result from increased intracranial pressure.
 Signs of meningeal inflammation are also present. The
onset of meningitis may be abrupt or insidious.
 Infants with meningococcal meningitis rarely display signs
of meningeal irritation and fever is typically absent in
children younger than 2 months of age (apneic episodes,
seizures and coma).
 Neurologic signs are common; convulsions, or signs of
meningeal irritation such as cervical rigidity (Brudzinski
sign) thoracolumbar rigidity, hamstring spasm (Kerning
sign) and exaggerated reflexes are common.
 Petechiae or purpura occur from the first to the third day of
illness in 30 -60% of patients.
 Fulminant meningococcemia (Waterhouse –
Friderichsen syndrome) occurs in 5-15% of
patients with meningococcal disease and has a
high mortality rate.
 It begins abruptly with high fever, chills, myalgias,
weakness, nausea, vomiting and headache.
 Apprehension, restlessness, and frequently
delirium occur within the next few hours.
 Widespread purpuric and ecchymotic skin lesions
appear suddenly.
 Typically, no signs of meningitis are present.
 Pulmonary insufficiency develops within a few
hours and many patients die within 24 hours of
being hospitalized despite appropriate antibiotic
therapy and intensive care.
Diagnosis
– Smears
– Culture
– Antigen Detection
Prevention and Treatment of
Meningococcal Disease
 Penicillin is the drug of choice for treatment in adjunct
with supportive therapy for meningeal symptoms
• Increasing MIC mediated by genetic alteration of
target penicillin binding proteins is being monitored)
• Chloramphenicol or cephalosporins as alternatives
 Chemoprophylaxis of close contacts with rifampin or
sulfadiazine (if susceptible)
 Polyvalent vaccine containing serogroups A, C, Y, and
W135 is effective in people older than 2 years of age for
immunoprophylaxis as an adjunct to chemoprophylaxis
• Serogroup B is only weakly immunogenic and
protection must be acquired naturally from exposure to
cross-reacting antigens
Epidemiology of Meningococcal
Disease
 Humans are the only natural hosts
 Person-to-person transmission by aerosolization of
respiratory tract secretions in crowded conditions
 Close contact with infectious person (e.g., family
members, day care centers, military barracks, prisons, and
other institutional settings)
 Highest incidence in children younger than 5 years and
particularly those younger than 1 year of age as passive
maternal antibody declines and as infants immune system
matures
 Commonly colonize nasopharynx of healthy individuals;
highest oral and nasopharyngeal carriage rates in schoolage children, young adults and lower socioeconomic
groups
Epidemiology
 N. meningitidis is normally present in the
nasopharynx of 5-10 % of normal individuals at
any given time, yet few develop disease.
 Carriage rates increase to 50% or more during
epidemics.
 Disease occurs sporadically or in epidemics.
 Most epidemics are caused by group A strains,
less so with B and C strains
 Group A, C, Y and W132 capsular polysaccharide
vaccines are available and can be used to control
outbreaks.
 The group B capsular polysaccharide is a
homopolymer of sialic acid and is not
immunogenic in humans.
 House hold contacts of cases are at 500-800 fold
greater attack rate, therefore should receive
chemoprophylaxis.
Moraxella
 Gram negative diplococci, oxidase and catalase positive
 They are commensals of mucosal surfaces and
occasionally give rise to opportunistic infections
 Most important species is M. catarrhalis
 It is associated with pneumonia, meningitis, endocarditis,
conjunctivitis, sinusitis, and otitis.
 It is occasionally isolated from the blood of
immunocompromised individuals.
Kingella and Eikenella
 Kingella are catalase negative, oxidase positive, and
glucose fermenting coccobacilli
 Kingella kingae is associated with endocarditis and
infection of bone, joints and tendons
 Eikenella corrodens is a small, oxidase positive, fastidious,
capnophilic gram negative rod that is part of the gingival
and bowel flora of 40-70% of humans
 It is found in mixed infections and those caused by human
bites