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Flashcards in meningitis agents of infant-->elderly Deck (90):
1

Streptococcus pneumoniae

Gram-positive, lancet-shaped diplococcus

Not fastidious, grows on blod agar – alpha hemolytic.

aerotolerant anaerobe - catalse negative

2

S. pneumo virulence factors

Encapsulated (90 serotypes):

antiphagocytic.

little or no crossreactivity among capsular types relates to possibility of multiple infections.

coagulase negative

3

S. pneumo Incidence and Prevalence:

Most common infectious agent associated with patients with *RECURRENT* meningeal infections.

Of the 7 major agents of bacterial meningitis, the *HIGHEST CASE FATALITY RATE* occurs with pneumococcal meningitis

4

S. pneumo peaks in what age groups ??

young (infants and children

5

S. pneumo Risk Factors

Patients may have:
antecedent RT infections → pneumonoccal pulmonary infections.

CSF leaks → recurrent meningeal infections
consistent with the presence of CSF

Invasive Pneumococcal Disease (IPD

6

CSF leaks occur in patients with:

history of head trauma.
congenital defect

*it is not uncommon to observe CSF leakage through ear or nose; If the fluid contains *β2-transferrin*, that finding consistent with the presence of CSF

7

a common complication of pneumococcal pneumonia that occurs in many (@25→ 30% of all) cases ??

meningitis?

8

Invasive Pneumococcal Disease (IPD)

Disease in which agent has been isolated from a normally sterile site:
blood
CSF
synovial fluid

9

S. pneumo pathogenesis

Primary site of damage is the hippocampus due to neuronal injury/loss via induced apoptosis

If pneumococcal bacteremia occurs, may produce petechial-purpuric skin lesions (AKA symmetrical peripheral gangrene (SPG) but no organisms are present in the lesion. (Indistinguishable in appearance from purpura fulminans caused by N. meningitidis, except that the pneumococcus is not in the lesion)

10

S. pneumo tx

IV cefotaxime (an extended-spectrum cephalosporin, 200 mg/kg/d) and continuous infusion vancomycin (60mg/kg/d after a loading dose of 15mg/kg) with adjunctive therapy with dexamethasone (10 mg every 6 hours) until strain is proven penicillin-sensitive (penicillins)

Adjunctive therapy with dexamethasone

Penicillin susceptible (PenicillinS) S. pneumo is treated with penicillin

11

Penicillin nonsusceptible S. pneumoniae (PNSP) include both

intermediately resistance to penicillin
full resistance to penicillin.

Resistance to other antibiotics also appeared along with penicillin resistance:

Trimethoprim-Sulfamethoxazole,
Macrolides; Erythromycin resistance is common (@ 20%) in USA
Fluoroquinolones

12

Drug-resistance S. pneumoniae (DRSP)

present and increasing in US

due to mutations in PBPs (AKA transpeptidases).

(Resistance to cephalosporins is also increasing, but may be effective)

Strains resistant to penicillin are often resistant to at least one other antibiotic, thus penicillin (the drug) resistance is a marker for resistance to several drugs

13

Multiply drug resistant (MDR) S. pneumoniae (MDRSP)

are resistant to >3 classes of antibiotics.

14

Vancomycin tolerance

(antibiotic is now static, no longer tidal):

First step in acquisition of vancomycin resistance is occurring in a small percentage of community-circulating strains.

Vancomycin tolerance occurs with penicillin, aminoglycoside and quinolone tolerance.

Clinically Important, related to relapses, esp. in pediatric cases of pneumococcal meningitis.

15

Prophylaxis to prevent S. pneumoniae disease:

23 valent polysaccharide vaccines (PPV23; Type II, T-cell independent antigen; Pneumovax or Pnu-immune) (pneumonia in elderly)

conjugated vaccine (T-dependent antigen; PCV-7 AKA Prevenar [7 valent vaccine]) is FDA approved and has resulted in a significant decreases in pneumococcal meningitis (kiddos)

16

Neisseria meningitidis – Meningococcal Meningitis spp.

Two pathogenic species:
N. meningitidis (the meningococcus).
N. gonorrhoeae (the gonococcus).

Nonpathogenic species:
NF of URT and other mucosal surfaces in the human body.
Many nonpathogenic species are non-encapsulated variants of the encapsulated/disease-causing strains of N. meningitidis

17

Characteristics of Neisseria meningitidis (the meningococcus):

Gram-negative diplococcus - kidney-bean shaped
oxidase positive
fastidious.

18

N. meningitidis Virulence factors and surface antigens

Group specific polysaccharide capsule (lipid moiety integrated into O.M.)

All infectious meningococcus are encapsulated and are grouped, based largely on the serological differences in capsular types.
Numerous groups exist; important groups:
*A, B, C, Y, W-135, X*

Capsular polysaccharide is antiphagocytic.

Group-specific antibodies do not significantly cross-react.

Type B capsule and E. coli K1 capsule have the same chemical composition (sialic acid); sialic acid is a human self antigen, hence are poorly immunogenic.

19

N. meningitidis Possess ??? instead of LPS

Lipooligosaccharide (LOS):

consists of Lipid A (endotoxin) + extended core (no antigenic side chain).

is antiphagocytic by molecular mimicry

causes Disseminated Intravascular Coagulopathies (DIC) because contains lipid A.


20

N. meningitidis Endemic patterns (in the US):

Case rate is low (0.5 → 1.1/100,000 population).

Major serogroups are *B, C, Y*
Serogroup B causes ½ of all infection in the US.

Serogroup Y infected patients are more likely to be older, manifest with pneumonia.

21

N. meningitidis Epidemic patterns:

countries where meningococcal disease is hyperendemic or epidemic – Africa and Middle Eastern countries.

in North America vs the rest of the world: Specific serogroups of meningococci are associated with epidemics, which occur in cycles.

22

N. meningitidis transmission

via aerosols, respiratory droplets

POE and initial site of colonization is the nasopharynx

23

N. meningitidis Host and source:

*humans* are the only reservoir for all Neisseria sp.
Non-immune and short-term, group-specific immune carriers exist.

Carrier state duration is highly variable (days → 10 m); chronic carriers do occur.
Carriers are common in epidemics, but few develop disease (1case/1,000 carriers).

*Non-immune and immune carriers* are largely responsible for spread of disease via aerosols because their numbers are so great vs. diseased patient

24

N. meningitidis age groups

infants and children (1 month → 24 months-o-age)

older children/adolescents (6 → 19 y-o-age).

young adults (19 → 22 y-o-age):
military recruits.
college students living in dorms.


25

N. menigitidis seasonality

Late fall → winter → early spring
(crowding)

26

N. meningitidis risk factors

Close contact, crowding → increased risk of exposure and infection.

Susceptibility (lack of group-specific antibodies):
living in a college dormitory or basic training in the military increases a susceptible persons’ increased risk of exposure to new groups of meningococci

27

N. meningitidis Undefined predisposing conditions: (FYI?)

antecedent RT may predispose host to infection,
intimate kissing.
tobacco smoke exposure (direct or pasive),
bar patronage,
household crowding,
binge drinking,
low socioeconomic status,

28

N. meningitidis: Susceptible populations in which disease predominates:

Infants → Young adults (1 month → 22 y-of-age).

Families (familial spread) and close contacts.

Genetic predisposition to infection and more severe disease is documented, i.e., some (20% of all) patients with meningococcal meningitis also possess properdin, complement (C3, homozygous C4b, C5, C6, C7, C8), or other deficiencies.
(esp. C5-C9-terminal)

29

N. meningitidis pathogenesis

After colonization of nasopharynx, the organism invades the blood (meningococcemia) and then from the blood, invades the meninges:

Thrombosis→DIC results from loss of thrombomodulin & protein C receptor (these are down-regulated by inflammatory cytokines). Thus activated protein C and not unactivated protein C is required to decrease DIC in your patient.

30

Immunity to N. meningitides is provided by several components of the immune system:

Humoral anticapsular antibodies are protective. Most adults have protective antibody to at least some groups.

Complement system is also necessary for protection.

31

Clinical Manifestations of Neisseria meningitidis
aged 16 years or younger:

Early symptoms of sepsis occurred in 72% of children at a median time of 8 hour:
leg pains.
cold hands and feet.
abnormal skin color.

Late symptoms: meningism and impaired consciousness occur about 13 to 22 hours after onset of early symptoms.

32

Clinical Manifestations of Neisseria meningitides: adults

Early symptoms may occur and consist of only mild pharyngitis without exudate, slight fever, and headache at onset
OR several days of flu-like symptoms with emesis

then the classic symptoms of meningitis occur
OR classic symptoms without early symptoms occur

33

Besides the classic clinical manifestations of meningitis, petechial (non-blanching, hemorrhagic) rash on ankles and wrist (first) then trunk, thigh, forearms may appear if ?? also present

septicemia

34

Patients may survive disease without or with significant sequelae from N. meningitidis, which include:

nerve deafness
CNS damage
necrosis of large areas of skin or tissues often results in amputation

35

Waterhouse-Friderichsen syndrome

fulminant meningococcemia characterized by:

circulatory shock due to SIRS → severe sepsis or septic shock.

bilateral hemorrhagic necrosis of adrenals → low cortisol leves → hypotension

disseminated intravascular coagulation

*not limited to N. meningitidis; this disease is seen in certain other fulminant bacterial diseases

36

Purpura fulminans AKA symmetrical peripheral gangrene (SPG): meningococcemia +/- meningitis: complications

hypothermia.
seizures.
shock.
thrombocytopenia.
leukocytosis.
purpura - meningococcus is in the lesions.

highest mortality rate (15→50%) occurs with Group C disease, esp. in persons with purpura fulminans, even with appropriate treatment

*not limited to N. meningitidis; this disease is seen in certain other fulminant bacterial diseases

37

Other meningococcal infections:

meningococcemia without CNS localization.

Meningococcus isolated from areas which are the domain of gonococci.

pneumonia or endocarditis.

38

Laboratory Diagnosis N. meningitidis:

Microscopic examination and culture of skin lesions (aspirant or biopsy)
If petechial or purpuric lesions are present, Gram-stain of lesion biopsy will often (50% of the time) reveal meningococcus (unlike S. pneumo, will NOT be in lesion)

Determine antibiotic sensitivity – resistance to many drugs is documented; *MBC required*

Obtain nasopharyngeal cultures to screen for carriers, treat carriers with rifampin

39

N. meningitidis tx

ceftriaxone, or cefotaxime or penicillin G

Other treatments: Bacteriocidal/permeability-increasing protein, recombinant rBPI

40

N. meningitidis morb/mort (with tx)

Among survivors, neurological sequelae/loss of limb is low (10→20%).

Mortality with uncomplicated meningococcal meningitis is low (10%)

Meningococcal meningitis with meningococcal septicemia; Mortality
without shock is high (20%).
*with shock is very high (60%)*

41

N. meningitidis ppx of HCW

Wear a mask (face shield) within 3 feet of pt. known or suspected to be infected with meningococcemia (or other microbial agent) transmitted by droplet nuclei (>5μ) that can be generated during coughing, sneezing, talking, performing clinical procedures. If no mask/shield is worn, consider antibiotic prophylaxis. Risk is small, but real, highest in those involved with airway management, i.e., the physician

42

N. meningitidis vaccines

Tetravalent/quadrivalent polysaccharide vaccine for Groups A, C, Y, W-135 ([MPSV4]; Menomune®

Tetravalent/quadrivalent (groups A, C, Y, and W-135) polysaccharide diphtheria toxoid conjugate vaccine [MCV4] Menactra®

43

Tetravalent/quadrivalent polysaccharide vaccine for Groups A, C, Y, W-135 ([MPSV4]; Menomune®

limitations??

a type II, T-independent antigen vaccine – Administered subcutaneous (SC)

limitations:

capsular material is a type II, T-independent antigen: Poor immunogenicity in infants (

44

Tetravalent/quadrivalent (groups A, C, Y, and W-135) polysaccharide diphtheria toxoid conjugate vaccine ([MCV4], Menactra®

Administered intramuscular (IM) – SC misadministration results in lower serum Ab titer. This is a T-dependent antigen vaccine

Vaccine is a T-dependent vaccine so should:

stimulate immunity for
eliminate nasopharyngeal carriage thus prevent transmission of infection.

Vaccine should reduce the prevalence of meningococcal disease by 75→ 90%.

45

Vaccines for protection against ?? infection are now approved by the FDA:

serogroup b

multivalent vaccines with OM components that either are common or rare but all are highly conserved in all strains of B

4CMenB vaccine (Bexsero):

Trumenba

46

The CDC advisory panel recommends that these serogroup B N. meningitides vaccines be administered to high risk populations such as ??

People with persistent complement component deficiencies.

Persons receiving the drug eculizumab (Soliris) also are at increased risk because the drug binds to C5 and inhibits the terminal complement pathway

Patients with anatomic or functional asplenia

People at increased risk owing to an outbreak of serogroup B meningococcal disease

not currently recommended for routine use in first-year college students living in residence halls, military recruits, or all adolescents; physicians should determine vaccination needs for 16-23 year olds on an individual basis; recommendations for broader use of MenB vaccines in adolescents and college students will be considered separately by the ACIP

47

Elimination of the carrier state (nasopharyngeal carriage of N. meningitidis ) by chemoprophylaxis with ??

timeframe??

rifampin, ciprofloxacin, or ceftriaxone or azithromycin
(unless fluoroquinolone-resistant N. meningitidis is detected in the area, if that is so, then ciprofloxacin should not be administered)

preferably within 24 hours of identification of the index case and no longer than 14 days after onset of illness in the index case and/or vaccination with Menactra of family members and close contacts of persons with disease.

48

For clusters (i.e., for children K → 12; a second case of meningococcal disease within 30 days of the first/index case) or small outbreaks, ppx with ??? is effective

abx

49

For large outbreaks (whole counties, cities, etc.), ?? (if the strain responsible for the outbreak is A, C, Y, W-135) as well as ?? of family members and close contacts of persons with disease are most effective.

vaccination
antibiotic prophylaxis

50

Cryptococcal meningitis caused by the fungus, Cryptococcus neoformans is usually a ??

subacute or chronic disease which is fatal if not treated

51

Cryptococcus neoformans

basidiomycete
(Cn) - Opportunistic pathogen that predominantly infect immunocompromised persons:

Cn variety (var):

*var. grubii* (CnVG; serotype A) - major causative agent worldwide.

var. neoformans (CnVN; serotype D) - prominent in central Europe.

var. AD, a hybrid diploid.

52

C. gattii

(Cg; serotype B and C; AKA Cryptococcus bacillisporus): A primary pathogen that predominantly infects immunocompetent persons

53

CnVN and CnVG distribution

Worldwide distribution (including rural and urban settings),

Found in soil, especially those enriched by avian guano, where it exists as a small (

54

Cg distribution

Previously thought to be restricted to tropical and subtropical climates with a special ecologic niche on Eucalyptus trees.

However, the recent outbreak of Cg infection in healthy humans (pneumonia &/or meningitis) and animals in the temperate climate of Vancouver Island, British Columbia, Canada and its isolation from several species of trees other than Eucalyptus as well as soil have raised the strong possibility that this fungus might have broader geographic distribution.

55

Cn Growth Characteristics:
The infectious form for humans and the pathogenic form in humans is the ??


Possess a sexual cycle, but ?? are NOT involved in infection or disease.

asexual yeast form.

Not thermally dimorphic, like other agents of systemic mycosis.

hyphae, spores

56

Crypto Virulence factors:

Capsule (glucuronoxylomannan GXM):
antiphagocytic
prevents antigen processing.

Phenoloxidase (laccase) production:
antiphagocytic.
results in increased resistance to amphotericin B
may also be responsible for agent’s neurotropism?

57

Cn/Crypto incidence/prev.
3rd most common cause of ?? after ??

4th most common ?? after ??

CNS infection in advanced HIV/AIDS patients after HIV and Toxoplasmosis

OI -opportunistic infection in advanced HIV/AIDS patients after P. jiroveci (PCP), CMV, M. avium complex.

58

Crypto Transmission and Reservoirs

For any strain of C. neoformans that can produce an infection in any patient population, person-to-person transmission is NOT believed to occur, even among AIDS patients.

Primary POE is the *RT* with hematogenous spread to CNS.

59

Crypto age, gender, seasonality

NONE

60

Crypto Risk Factors: Cg (gatti)

causes cryptococcosis in *immunocompetent* individuals in tropical/subtropical regions (e.g., California in the US).

incidence of disease is rare, but increasing.

rarely causes disease in advanced HIV/AIDS pt (explanation unknown).

no predisposing factor(s) known.

61

Crypto Risk Factors: CnVN AND CnVG:

case distribution is sporadic and worldwide

rarely causes disease in immunocompetent patient.

causes cryptococcosis in *immunocompromised or immunosuppressed* individuals:

62

immunocompromised/immunosuppressed individuals (@ risk for Crypto -CnVN and CnVG) include:

Impaired cell-mediated immunity:

advanced HIV/AIDS,;

lymphoreticular malignancies,

patient receiving chronic, high-dose corticosteroid,

immunosuppressive therapies for SOT pts

Infection and disease occurs in some (@ 5→10% of) advanced HIV/AIDS patients → a persistent infection.
Advanced HIV/AIDS pt. that survives initial presentation requires life-long therapy.

63

primary sites of infection for var. grubii and var. neoformans:

lungs and CNS

(Primary POE is the respiratory tract with hematogenous spread to CNS)

64

In immunocompetent patients w. Cn

asymptomatic pulmonary infection are usual.

65

In immunocompromised patients, especially advanced HIV/AIDS patient, with Cn

disease is more common and progression of disease tends to be more rapid

Lung infections are variable: mild, sustained febrile illness with normal radiographs → fulminant course with shock and/or ARDS.

Most commonly in the AIDS patient, S/S similar to PCP; Over 2 → 4 weeks, symptoms develop:
fever,
cough
dyspnea
weight loss,
headache.

CXR reveals interstitial infiltrates (focal or diffuse).

66

Cn Meningoencephalitis:
involves ??
ICP??

A progressive infection mostly involving basal ganglia and cortical gray matter:

Elevated Intracranial pressure (ICP) >250 mm H2O is common and a significant cause of mortality in these patients.

67

Cn Meningoencephalitis presentation

Usually subacute with insidious onset. Over 2 → 4 weeks, symptoms develop:
headache.
fever.
lethargy.
nausea, vomiting.
minimal nuchal rigidity.

symptoms progresses on to focal signs:
personality change (altered mental status-behavior)
impairment of higher mental functions (memory, cognition, language)

ends with coma and death.

68

Cn in In advanced HIV/AIDS and severe T-cell compromised patients:

Besides the 2 primary sites which are the Lungs and CNS:


Organism is much more likely to disseminate to any organ, especially:

skin (every kind of lesion is possible: cutaneous cryptococcosis] may mimic many cutaneous disorders, including

molluscum contagiousum, acne vulgaris, squamous cell cancer, or even cellulitis (can be the sentinel finding of disseminated disease)

also:
eye
bone
urinary tract

69

Cryptococcal polysaccharidemia/antigenemia:
(In advanced HIV/AIDS and severe T-cell compromised patients)

positive serum antigen assay without detection of fungi from any body site (i.e., negative results by visualization or growth or histochemical staining).

Occurring with increasing frequency in advanced HIV/AIDS infected patient due to increased antigen testing.

There is no data on how many persons with antigenemia will develop disease

Since this is a fatal disease and treatment is available, *all patients with positive serum antigen must be treated*

70

Crypto: EC or IC?

faculataitve intracellular pathogen of macrophages:

can replicate in the phagosome of macrophages → macrophage lysis and release of the agent.

An extrusion/explusion mechanism allows the agent to be released from macropahges without lysing the macrophage and avoiding a host inflammatory responses.

71

ddx meningoencephalitis for an AIDS patient:

HAD (HIV-assoc. dementia):

Primary or metastatic brain tumor – EBV-associated primary CNS lymphoma.

Toxoplasmosis encephalitis

PML

Cryptococcal meningoencephalitis

CMV polyradiculopathy, encephalitis, myelopathy, etc.

72

for Crypto dx, obtain samples of:

CSF
blood,
urine,
sputum and other respiratory samples,
biopsied tissues.

73

Test cypto samples by:

Serologic tests (latex agglutination test, ELISA) to detect presence of capsular antigen:
serum CrAg-Its presence is highly predictive of development of CM within 1 yr.

Culture on routine mycological or bacteriological media (blood agar).

Microscopic examination of sedimented CSF:
-with India ink preparation reveals 5→7 μm spherical, capsulated yeasts forms
cells of macrophage/monocyte lineage.
-by Gram-stain reveals Gram-positive eucaryotic cells:
(All yeast, including cryptococcus, stain Gram-positive by Gram stain)

Others:
Mucicarmine stain.
Papanicolaou prep.
Hematoylin and eosin (H/E).

74

Crypto Radiology:

CXR or CT for pulmonary involvement

CT or MRI for meningitis.

75

Crypto tx

High dose amphotericin B (0.7mg/kg IV) with 5-fluorocytosine (100mg/kg/day) for 2w.

Fluconazole (400mg PO) or itraconazole for 8 weeks.
-Maintain with fluconazole (200mg PO daily) life-long unless relapse occurs.

Drug resistance is rare.
Treat elevated ICP.

Prognosis is poor in the absence of HAART: 10-25% die during initial presentation and 30-60% succumb within 1 year.

76

Crypto prevention

NONE

77

AMOEBIC and ACUTE PRIMARY MENINGOENCEPHALITIS

A very rare diseases confined to the CNS that is produced by amoebae (protozoa).

78

Amoebae possess 2 cellular forms:

trophozoites are the feeding form found in brain and in the environment

cyst are the resistant form found in water, NEVER BRAIN
-resistant to freezing water and chlorination

79

Naegleria fowleri

ubiquitous, free-living amoebae found in warm, freshwater lakes, puddles, ponds, improperly chlorinated swimming pools and brackish water especially during *hot weather summers*

80

Population at risk for acute primary amoebic meningoencephalitis:

Children and young adults;

Seasonal occurrence = summer - swimming/waterskiing in warm, fresh water.

Patients are usually healthy, immunocompetent before disease (but immunocompromised persons are equally susceptible).

1/2 of all cases worldwide occur in the US (~1case/y in the US until last year; when 6 cases occurred).

81

Acute primary amoebic meningoencephalitis (PAM) Infections occurs when water bearing the agent forced into the POE which is the ???

nose-->the organism is implanted in the nasal mucosa from which it invades the CNS through the cribriform plate and can be found in the subarachnoid and perivascular spaces. (*Inflammatory disease*)

82

acute PAM disease duration ??

incubation period??

manifests with ??

death from ??

Fulminate course 2 → 7 days from onset of symptoms to death.

After a short (2 → 4 d) incubation period, patient manifests with s/s similar to those of acute bacterial meningitis and/or encephalitis.

1 → 2 days after symptom first appear, pt. manifests with diffuse encephalitis then coma.

Death occurs 2 → 7 days later due to cardiorespiratory failure, cerebral edema.

83

dx PAM

difficult due to non-specific symptoms and rapid progression of disease

84

?? is essential in diagnosis of PAM

Patient history:

Hyperacute clinical course.
Unrelenting signs and symptoms.
Exposure to fresh water

85

In PAM: CSF findings similar to those of bacterial meningitis (PMNs predominate, etc.) except may observe ???
also:

amoeba in CSF:

Cloudy fluid.
PMNs predominate
Hyperproteinosis (elevated protein levels).
Hypoglycorrhachia (low glucose).
*Absence of viral, bacterial or fungal agents*, none detected by staining, culture, PCR, rapid tests, etc.


86

other PAM dx clues

Peripheral leucocytosis
*Death within a week*

87

PAM Brain biopsy specimen reveals:

Positive IFA test with anit- Naegleria fowleri serum.

Clusters of amoebic trophs by H/E stain

Intense PMN infiltrate/inflammation in brain parenchyma

88

PAM px

Prognosis is very poor – high mortality, those who survive have catastrophic, irreversible brain damage.

89

PAM tx

Amphotericin B - intrathecally and/or intraventricularly

Miltefosine

90

Miltefosine:

An investigational antineoplastic drug (breast cancer) and antiprotozoal drug (anti-leishmania drug and N. flowerii), now HIV therapy by targeting HIV infected macrophages:

Akt inhibitor/Protein Kinase B (PKB), a serine/threonine-specific protein kinase

Miltefosine targets HIV infected macrophages, which play a role in vivo as long-lived HIV-1 reservoirs. The HIV protein Tat activates pro-survival PI3K/Akt pathway in primary humanmacrophages. Miltefosine acts by inhibiting the PI3K/Akt pathway, thus removing the infected macrophages from circulation, without affecting healthy cells.

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