Neisseria
Características Gerais do Gênero
Neisseria
 Aeróbico
 Cocos Gram-negativos com arranjo aos pares
(diplococos) com os lados adjacentes planos
(forma de rim ou feijão)
 Oxidase positiva
 Catalase positiva
 Imóveis
 Formam ácido a partir da oxidação de
carbohidratos (não da fermentação)
Patógenos Humanos
Neisseria gonorrhoeae
Neisseria meningitidis
Outras espécies colonizam as mucosas do
orofaringe, nasofaringe e anogenitais
Doenças Associadas a Neisseria
(ophthalmia neonatorum)
Características Diferenciais das
Espécies de Neisseria spp.
Neisseria gonorrhoeae
(gonococcus)
Aspectos Gerais da Infecção
por Neisseria gonorrhoeae
 Transmitida por contato sexual
 Cocos Gram-negativos aos pares com
morfologia característica
 Fastidiosos, capnofílicos e susceptíveis a
baixas temperatures, ressecamento e ácidos
graxos
Meios complexos pré-aquecidos a 35-37C
Amido solúvel adicionado para neutralizar ácidos graxos
Crescem melhor em atmosfera suplementada com CO2
 Produzem ácido a partir da glucose, mas não a
partir de outros açúcares
Exsudato Uretral - Neisseria
gonorrhoeae
Epidemiologia da Gonorréia
 DST com sub notificação
 Acomete apenas seres humanos com aspectos
epidemiológicos diferentes em homens e mulheres
 Portador assintomático é reservatório
 Transmissão por contato sexual
 Possibilidade de re-infecção pela diversidade
antigênica das cepas
 Alto risco de disseminação em pacientes com
deficiência de complemento
Incidência de Gonorréia nos EUA
Diferenças da Epidemiologia entre
Homens e Mulheres
Homens:
 Uretrite; Epididimite
 A maioria das infecções são agudas e
simtomáticas com descarga purulenta e disúria
após 2-5 dias de período de incubação
 Homens procuram tratamento precocemente,
previnindo sequelas, mas não tão cedo a ponto de
previnir a transmissão a outros parceiros sexuais
 Agentes bacterianos responsáveis por uretrite em
homens: N. gonorrhoeae , Chlamydia trachomatis
e Mycoplasma genitalium
Diferenças da Epidemiologia entre
Homens e Mulheres
Mulheres:
 Cervicite; Vaginite; Doença Inflamatória Pélvica
(DIP); Infecção gonocóccica Disseminada
 Mulheres frequentemente assintomáticas ou com
manifestações atípicas; Não tratadas até outras
complicações se desenvolverem, como DIP
• Pode levar a lesões nas trompas de Falópio levando a
infertilidade ou gravidez ectópica
Diferenças da Epidemiologia entre
Homens e Mulheres
Mulheres:
 Infecção Gonocóccica Disseminada:
•
•
•
•
•
•
•
Resultado de bacteremia
Lesões cutâneas
Petéquias
Pústulas nas extremidades
Artralgia
Tenosinovite
Artrite séptica
Gonorréia
Females
Males
50% risk of infection after single exposure
20% risk of infection after single
exposure
Asymptomatic infections frequently not
diagnosed
Most initially symptomatic (95% acute)
Major reservoir is asymptomatic carriage
in females
Major reservoir is asymptomatic
carriage in females
Genital infection primary site is cervix
(cervicitis), but vagina, urethra, rectum
can be colonized
Genital infection generally restricted to
urethra (urethritis) with purulent
discharge and dysuria
Ascending infections in 10-20% including Rare complications may include
salpingitis, tubo-ovarian abscesses, pelvic epididymitis, prostatitis, and
inflammatory disease (PID) , chronic
periurethral abscesses
infections can lead to sterility
Disseminated infections more common,
including septicemia, infection of skin and
joints (1-3%)
Disseminated infections are very rare
Can infect infant at delivery (conjunctivitis, More common in homosexual/bisexual
opthalmia neonatorum)
men than in heterosexual populatiuon
Patogênese da Neisseria gonorrhoeae
 Células com fímbrias aderem ao tecido epitélial
intacto das mucosas
 Capacidade de invadir o epitélio ou a pele com
abrasões
• Aderência ao epitélio das mucosas
• Penetração e multiplicação nas células epiteliais das
mucosas
• Infecção estabelecida na camada sub-epitelial
 Sítios mais comuns de inoculação:
• Cérvice (cervicite) ou vagina em mulheres
• Uretra (uretrite) ou penis no homem
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.)
 Lipooligosaccharide (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
Laboratory Characterization
 Small, gram-negative diplococci in presence of
polymorphonuclear leukocytes (PMN’s) seen
microscopically in purulent urethral discharge
 Susceptible to drying and cooling, so immediate
culture of specimen onto pre-warmed selective (e.g.,
modified Thayer-Martin, Martin-Lewis agars) and nonselective media (chocolate blood agar) with moist
atmosphere containing 5% carbon dioxide
 Some strains inhibited by vancomycin (in many selective
agars) and toxic substances like fatty acids and trace
metals in protein hydrolysates and agar found in
nonselective media
 Five morphologically distinct colony types (formerly T1
through T5) that can undergo phase transition are no
longer considered to be a useful distinction
Prevention & Treatment
 Penicillin no longer drug of choice due to:
• Continuing rise in the MIC
• Plasmid-encoded beta-lactamase production
• Chromosomally-mediated resistance
 Uncomplicated infxn: ceftriaxone, cefixime or fluoroquinolone
 Combined with doxycycline or azithromycin for dual infections
with Chlamydia
 Chemoprophylaxis of newborns against opthalmia
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
Analytic Performance of
Different Laboratory
Detection Methods for
Nesseria gonorrhoeae
NOTE: Importance of
Sensitivity vs. Specificity
for any Diagnostic Test
Analytic Performance
of a Diagnostic Test
ACTUAL
ACTUAL
POSITIVE NEGATIVE
TEST
POSITIVE
80
True
Positives
TEST
20
NEGATIVE
False
Negatives
100
TOTALS
Actual
Positives
25
False
Positives
75
True
Negatives
100
Actual
Negatives
TOTALS
105
Test
Positives
95
Test
Negatives
200
Analytic Performance
of a Diagnostic Test (cont.)
Sensitivity = Measure of True Positive Rate (TPR)
= No. of True Pos. =
No. of True Pos.
=
80 = 80%
No. of Actual Pos.
No. of (True Pos. + False Neg.) 80+20 Sensitivity
In conditional probability terms, the probability of a positive
test given an actual positive sample/patient.
Specificity = Measure of True Negative Rate (TNR)
= No. of True Neg. =
No. of True Neg.
= 75 = 75%
No. of Actual Neg. No. of (True Neg. + False Pos.) 75+25 Specificity
In conditional probability terms, the probability of a negative
test given an actual negative sample/patient.
Neisseria meningitidis
(meningococos)
Visão Geral da Neisseria meningitidis
 Diplococos Gram-negativos encapsulados e pequenos
 Segunda causa mais comum (após S. pneumoniae) de
meningite adquirida na comunidade; progressão
abrupta de estado de saúde para doença gravíssima
 Pathogenicity:
• Colonização de células não-ciliadas do
nasofaringe mediada por pili
• Cápsula antifagocitária (de polissacarídeos)
permite espalhamento sistêmico na ausÊncia de
imunidade específica
• Efeitos tóxicos mediados pela hiperprodução de
lipooligossacarídeos
 Sorogrupos A, B, C, Y, W135 respondem por 90% de
todas as infecções
Doenças Associadas a Neisseria
meningitidis
Seguindo a disseminação de organismos
virulentos a partir da nasofaringe
 Meningite
 Septicemia (meningococcemia) com ou sem
meningite
 Meningoencefalite
 Pneumonia
 Artrite
 Uretrite
Neisseria meningitidis no
Líquido Céfalo-Raquidiano
Epidemiologia da Doença Meningocóccica
 Humanos são os únicos hospedeiros naturais
 Transmissão pessoa-a-pessoa por aerossóis de
secreções respiratórias
 Contato próximo com pessoas infectadas (p.e.
membros da família, em creches, acampamentos
militares, prisões, etc)
 Maior incidência em crianças com até 5 anos
 Comumente coloniza nasofaringe de indivíduos
saudáveis; alta taxa de colonização oral e de
nasofaringe em crianças com idade escolar, adultos
jovens e grupos com condições sócio-econômicas
baixas
Distribuição Etária da Doença
Meningocóccica
Lacking maternal antibody
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
Laboratory Characterization of
Neisseria meningitidis
 Large numbers (e.g., >107cells/ml) of encapsulated,
small, gram-negative diplococci (flattened along
adjoining side) and polymorphonuclear leukocytes
(PMN’s) can be seen microscopically in
cerebrospinal fluid (CSF)
 Transparent, non-pigmented nonhemolytic colonies
on chocolate blood agar with enhanced growth in
moist atmosphere with 5% CO2
 Oxidase-positive
 Acid production from glucose and maltose but not
from other sugars
Prevention and Treatment of
Meningococcal Disease
 Penicillin is 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