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patho exam 4 > bug parade part 2 > Flashcards

bug parade part 2 Flashcards

1
Q

C. Diff characteristics All clostridial species are Gram-______!

A

positive

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2
Q

C. Diff characteristics poisened by oxygen they are ________ _____?

A

obligate anaerobe

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3
Q

C. Diff characteristics _______ _______ and produces 2 _____?

A

Spore former toxins

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4
Q

C. Diff characteristics What are the two toxins produces by the Gram positive, Spore- Forming, clostridial species?

A

A-entrotoxin BAB cytotoxin

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5
Q

C. Diff characteristics Many strains are still susceptible to ________ but are quickly becoming a major problem in ______, many countries now recognize it as a __________?

A

antibiotics hospitals Superbug

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6
Q

C. Diff Disease and Ecology Clostridium difficile was first isolated in ______ from _____ _______?

A

1935 infant stool

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7
Q

C. Diff Disease and Ecology Clostridium difficile was first recognized as a pathogen in the year _______ when it was isolated from ______, ______,______, and _______ ____ of patients with a variety of illnesses, However it was still not a problem.

A

1960 wounds abscesses blood

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8
Q

C. Diff Disease and Ecology Clostridium difficile was first associated with causing ________ ________ or _ _ _?

A

pseudomembranous colitis PMC

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9
Q

C. Diff Disease and Ecology The first association between C. difficile and PMC was in the year _____? the same year C. difficile was isolated from patients with the illness or experiencing ________ ________?

A

1978 Postoperative diarrhea

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10
Q

C. Diff Disease and Ecology Clostridium difficile was recognized as ______ _____ in the 1960’s-70’s but was not taken seriousley till the ________?

A

antibiotic resistance 1980’s

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11
Q

C. Diff Disease and Ecology one of the side effects of antibiotic use is the Disruption of normal protective ______ _____. so while antibiotics are successfully treating one cabterial infection could cause antoher infection in the same patient.

A

resident flora

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12
Q

C. Diff Disease process 1. After ingestion _____ _____ are killed by stomach acid but _____ survive.

A

vegetative cells spores

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13
Q

C. Diff Disease process 2. ________ germinate in the ____ _____ upon exposure to _______ acids?

A

Spores small bowel bile

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14
Q

C. Diff Disease process 3. Movement is made from the Small bowel to the _____ by the use of _____. The ______ _____ protects the organisum from _______?

A

Colon Flagella Polysaccharide capsule phagocytosis

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15
Q

C. Diff Disease process 4. Organisms ________ in the colon and adhere to ______ ____?

A

multiply epithelial cells

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16
Q

C. Diff Disease process 4. After adherence to the epithelial cells of the colon the organisum creats a local producation of ________ ____ and _____, production of ______, _____, ______ ____ _____ , ____ and _____ _____.

A

toxins A B a-TNF Inflammation Increased vascular permeability neutrophile monocyte recruitment.

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17
Q

C. Diff Disease process 5. After production of toxins and adherence Opening of the _____ ____ ____ and cell _____?

A

epithelial cell junctions apoptosis

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18
Q

C. Diff Disease process 6. After opening of the epithelial cell junctions and cell apoptosis local production of ____ _____ cause ______ _____ _______?

A

hydrolytic enzymes connective tissue degradation

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19
Q

C. Diff Disease process 7. connective tissue degradation leads to ______ , _______ _____ ( dead tissue, fibrin, mucus phagocytes, DNA) and watery ______?

A

Colitis pseudomembrane formation diarrhea

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20
Q

C diff

Disease process

Breakdown of the epithelium mainly by the action of ____ _ allows entry of ____ _ to underlying tissue causing yet more damage?

A

toxin A

toxin B

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21
Q

C diff

Disease process

With extensive damage ____ _____ or other _______ form the colon can pass into the blood ( and in addition to strong inflammatory response due to tissue dmage) cause ____ _____

A

LPS (gr-ve)

bacteria

septic shock

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22
Q

C diff

Disease process

Strain variations include _____ and ______ _____ strains?

A

toxogenic

non toxogenic

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23
Q

C diff

Disease process

1-5% normal population harbor this organisum this raises to 20% in ____ _____. and has now spread to the community.

A

hospital enviroment

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24
Q

CDAD is also know as _______?

transmission is spread from ____ to ____- via ______ ____ route

A

c. difficile associated Disease

person

person

fecal oral

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25
Q

_____ ________ is a severe ulceration of the colon, described 100 yrs ago and still rare until 1970.

fatal within a few days

-

A

pseudomembranous colitis

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26
Q

pseudomembranous colitis

accumulation of ____, ____ , ___ ___ ___ -yellow layer on surface of mucosa.

A

fibrin

mucin

dead host cells

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27
Q

Pseudomembranous colitis

Separate ________ become more widespread becoming the ________. fatel within a few days is not treated.

A

leasions

pseudomembrane

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28
Q

Pseudomembranous colitis

______ may be so sever that the ____ _____ becomes distended and the ____ _____ _____?

A

inflammation

large bowel

bowel wall thins

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29
Q

Pseudomembranous colitis

when the bowel becomes distended and the bowel wall thins ____ _____ can occure this carries a risk of ____ ___ and _____ ?

A

toxic megacolon

bowel perforation

peritonitis

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30
Q

Virulence factors of C. diff

  1. A and B toxins

toxins A and B are the _______ ____ ___ toxins known.

A

largest single molecule

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31
Q

Virulence Factors

Toxins A-B

Toxins A-B Modeify membrane ____ ______ that control many cellular activities?

A

G protein

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32
Q

Virulence Factors

Toxins A-B

Unlike many toxins these types were difficult to work on ( tend to aggregate, elude purification) untillgenes cloned and characterized _____ and _____?

A

tcdA

tcdB

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33
Q

Virulence factors

Toxin A-B

This Activates enteric _______ affecting _______ of _______ contents thus contributing to ________?

A

nerons

motility

intertinal

diarrha

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34
Q

Virulance factors

Toxin A-B

Attract/activates PMN’s by __________ - this causes an ________ response that leads to ______ _____ ______?

A

cytokines

inflammatory

mucosal cell destruction

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35
Q

Virulance factors

Toxin A-B

Effects motility of intestinal contents causing ________ of _________ into ______ _________?

A

leakage

water

lumen diarrhea

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36
Q

Virulance Factors

Toxin B

Toxin B Collapses ____ ______, so the shape of the cells lost?

A

actin cytoskeleton

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37
Q

Virulence Factors

Toxin B

Toxin B damages underlaying tissue of the ____ _____ and ____ ____?

A

mucosal membrane

intersinal wall

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38
Q
A
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39
Q

Lethal hospital bug cases rocket, United Kingdom

-Potentially lethal cases of C.diff rocketed from 1990- ______?

Cases had increased from 1,000 in 1990 to over 35,000 in ______?

-45,000 cases of ___ ___ in ___ year olds in 2004?

A

2004

2003

C. difficil

>=65

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40
Q

C. difficil Outbreaks

2007- United Kingdom

-the number of deaths linked to the hospital infection ____ ____ more than doubled in the previous two years.

A

Clostridium difficil

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41
Q

2007- United Kingdom

England and Wales 8,324 people died from either _ _____ or were infected with it when they died from other causes - a rise of ____ percent in just one year.

A

C. Diff

28

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42
Q

2007 -United Kingdom

The infection which particularly affects ____ people increases _____ times over 2001 when 1,804 deaths where linked to the _______?

A

elderly

4

superbug

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43
Q

The general public are now more aware of ___ ______- but ____ is the key to prevention?

A

C. difficile

education

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44
Q

2007 -United Kingdom

The third major outbreak in 2007 occured in ____ _____ ?

A

maidstone hospital

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45
Q

C. diff

Prevention and treatment

  • Early diagnosis- ________ associated diarrhea- routine monitoring for __ &_____ _________ in feces?
A

antibiotic

A

B

Toxins

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46
Q

C. Diff

Prevention and Treatment

Replace antibiotic causing problem with _______ or ______ this kills c. difficil but does not adversely affect ______ ______?

A

vancomycin

metronidazole

normal flora

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47
Q

C. Diff

Prevention & treatment

-Relaspes (multiple) in _____ ____ % of patients?

A

10-20

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48
Q

C. Diff

Prevention & treatment

Failure to clear C. difficile and restore stable, _____ _______ leads to _____ _____?

A

nonpathogenic flora

resistant spores

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49
Q

C. Diff

Prevention & treatment

Treatment is best when coupled with improved _____ ____ within ______?

A

cleaning practices

hospitals

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50
Q

C. Diff

Alternative therapy

One of the Alternative therapies for C. diff treatment is to _______ ____ ___- using an enema containing dilute feces from a family member?

A

Replace resident flora

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51
Q

Alternative therapies

C. diff

Replacement of resident flora using an enema containg dilute feces is referred to as ____ ____ or ____ _____ _______?

A

Fecal Bacteriotherapy

Fecal Microbiota transplantation (FMT)

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52
Q

An _________ is the procedure of introducing liquids into the rectum and colon via the anus?

A

enema

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53
Q

Fecal bacteriotherapy/ Fecal microbiota transplantation (FMT)/

replacemant of resident flora using an enema containing dilute feces from a family member Previously used in health clinical for so called _______ ____ but now is accepted and widely used treatment for C. diff infections?

A

detox Therapy

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54
Q

what is Pulse Net

A

detection of Foodborn Diseases by Pulsed field Electrophoresis (PFGE)

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55
Q

Potential reasons for increased CDAD, incidence and severity

Historical

changes in underlying ____ ________?

and changes in ____ _______?

A

host susceptibility

antimicrobial prescribing

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56
Q

potential reasons for increased CDAD, incidence and severity

Recent

  • New strain with increased _____
  • _ _ _ -binary toxin
  • variations in _ _ _ _ activity
  • changes in ____ ____ ______
A

virulence

CDT

TcdB

infection control prctices

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57
Q
A
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58
Q

treponema pallidum

Is A ________ bacterium with subspecies that cause treponemal diseases such as __________

A

spirochaete

syphilis

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59
Q

spirochetes

are gram ________ , they are _____ _______ shaped with a Motile , ______ style of movement?

A

negative

Thin helical

corkscrew

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60
Q

internal flagella

what two spirochete organisums where listed with internall flagella and what do they cause.

A

Borrelia burgdorferi -Lyme Disease

Treponema pallidum- Syphilis

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61
Q

TTreponema pallidum

Treponema pallidum is never cultured in the laboratory on ____ _____

Insted it isw cultured on tissue culture cells of ____ ____ _____?

A

artificial media

cottontail rabbit epithelium

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62
Q

Treponema pallidum is known to cause _______ and is only found in ____ ____ ?

A

syphillis

human host

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63
Q

Syphillis is caused by ____ ____ is Extremly sensitive to ____ ____, and is transfered ______ to ______ by _____ ______?

A

Treponema pallidum

enviromental stress

person

person

sexual contact

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64
Q

Syphillis is often transferred with ____ _______ but potentially is much more serious.

A

N. gonorrhoeae

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65
Q

Shypillis is most prevalent among____ and _____ _____?

A

minority

ethnic populations

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66
Q

Syphilis is 60X higher in ___ ____ than in ________?

A

African american

caucasins

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67
Q

80% of syphilis is in the ______ United states?

A

southern

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68
Q

Morphology, physiology and motility:

even though Treponema pallidum is gram negative it still has a small amount of _____ ____ between _ _____?

A

Peptidoglycan

2 membranes

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69
Q
A
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70
Q

Morphology, physiology and motility:

Treponema Pallidum has a ______ _______ that makes up the cell body it is ______ and generally ________?

A

protoplasmic cylinder

rigid

generally helical

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71
Q

Morphology, physiology and motility:

A
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72
Q

Morphology, physiology and motility:

Spirochetes such as Treponema pallidum has 1 to many ______ ______ that emerge from poles called _________?

A

internal flagella

Endoflagella

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73
Q

Morphology, physiology and motility:

Spirochetes are covered by a multilayered, flexible membrane called an _____ _______?

A

Outer sheath

this is important to avoid the immune system. most bacteria have many things attached to thier outer membrane( sugars ect. )

Treponema pallidum Has a smooth outer membrane with not many sugars or receptors ….. not many targets for the immune system

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74
Q
A
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75
Q

Morphology, physiology and motility:

Endoflagella ___________ the _____ ________ is rigid and the _____ ________ is flexible. When flagella rotate in the same direction, the protoplasmic cylinder rotates in the _____ _______?

A

rotate

protoplasmic cylinder

outer sheath

opposite direction

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76
Q

Morphology, physiology and motility:

tension placed on the cell causes ________, _____ ,____ _____ movement?

A

flexing

twisting

jerky corkscrew

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77
Q

Morphology, physiology and motility:

The twisting , jerky corkscrew movement is effective in _____ ____, _____ and _____?

A

viscous solution

blood

tissues

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78
Q

diagnosticaly how are Ricketts and shypillis diffrent?

A

ricketss rash all over but not on palms and feet

shypillis rash primarily on hands and feet

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79
Q

in 2008 the CDC estimates Total infections at _____ million with _____ million new annual infections costing the United states a total of _______ ____ in medical cost?

A

20

110

$16 billion

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80
Q

History

Syhillis is considered an ____ ___ for the _____ centery with the surge of mankind, but became a even bigger problem in _______?

A

Old disease

15th

1960’s

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81
Q

History

shypillis infections increased in the 1960’s because of the _____ _____ and the invention of the _____ ____?

A

sexual revolution

contraceptive pill

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82
Q

History

The 1960 caused a sexual revolution with the invention of the ____ ____ which led to ______ ____ ____ (control when /if to have kids)

and it also led to an increase in ________?

A

contraceptive pill

increased sexual activity

prostitution

83
Q

disease progression

Disease progression of shypillis has similarties to ____ _______, Both caused by ______, however they are diffrent ________?

A

Lyme disease

spirochetes

genera

84
Q

Disease progression

Both ______ _____ and ______ have ______ _____ in thier life cycles?

A

lyme disease

syphilis

multiple stages

85
Q

History

shypllis

first outbreak was in _______ on the year ______ also called the ______ ____ due to it causeing large sores compared to ________?

A

london

1748

great Pox

Smallpox

86
Q

History

During the Great Pox outbreak in London in 1748 the causes , of this along with many other illness whas not understood. many belived the causes to be ?

A

hand of God

Astrological events

Curses

Gaseous emmissions, miasms- noxious bad air

87
Q

An infamous experiment– John Hunter, Physician
Hunter hypothesized that two diseases could not exist simultaneously in the same
organ. Therefore syphilis and gonorrhea were believed to be different symptoms
of the same sexual illness.
Dry –chancre or Wet –discharge?
Had a theory that is was one disease that was transferred by the
discharges observed. So, he needed a healthy penis….!
He took some discharge from a male patient and transferred it to
the glands of his own penis…
He then stabbed himself with a lancet, several times !! and then
squeezed the cut open with the liquid discharge could enter !!

A

In a few day he reported a “tingling” in his penis followed a few
days later by two chancres
Treated himself with mercury.
3 mths later he got a skin rash, treated again with massive dose of
mercury
-he reported that the symptoms had disappeared for good ?..
Approx. 25yrs later – he died of syphillis and possible mercury
poisoning!!

88
Q

virulence factors

ability to _______ _____ to invade the body

  • Ends of the bacteria attach to the _____ ____ containing ______ ____ that joins capilillary _____ _____?
A

transit epithelia

hyaluronic acid

extracellular matrix

endothelial cells

89
Q

Virulence factors

the ______ ______ allows the organisum to cross tissue layers and enter and exit bloodstream.

-it also has the ability to cross the _______

A

corkscrew motility

placenta

90
Q

Primary syphillis

T, pallidum ________ pass through unbroken skin. infection probably occurs via small tiny breaks in the ______ ____ caused during sexual activity?

for males this is the _______?

Females____ , _____ and surrounding regions

____% of cases extra _______, usally _____ and _____ regions

A

cannot

epidermal layer

penis

vagina

cervix

10

genital

oral

anal

91
Q

Sypillis has the ability to cross the placenta and infect the fetus- this is called ____ ______

first noticed symptoms as _____( irritation and inflammation of the _____ )and then ____?

A

congenital syphilis

rhinitis

nose

rash

92
Q

untreated infants who survive syphillis show signs of ____ _____, ______and ________ malformations, ________, _______, and ___________ syphilis

A

cronic infection

teeth

bone

blindness

deafness

cardiovascular syphilis

93
Q

T. Pallidum _______ at the sire of entry and a characteristic _______ (______ ) is formed within ____weeks to ____ months?

A

multiplies

lesion

chancre

2

2

94
Q

The lesion(chancre) maybe hidden on _____ under the ______, ____, ____ or _____?

A

scapl

hair

vagina

anus

mouth

95
Q

a false sense of relief for the patent when the ______ disapperears after a few ______ and heals spontaneously during this time _____ are migrating away from the site of infection.

patient is infectious

A

chancre

weeks

bacteria

96
Q

Secondary syphilis

1-3 months

-Bacteria penetrate _____ ______ and enter _________?

_Bacteria spread to mucous membranes ,____, ______, ____ or _ _ _?

A

mucosal membranes

bloodstream

eyes

joints

bones

CNS

97
Q

Secondary syphilis

  • Body mounts an _____ _____ causing ____ like symptoms- _____ ____, ______, _____,____ ____ ____?
A

immune response

Flu

sore throat

headache

fever

swollen lymph glands

98
Q

Secondary syphilis

Key features include ?

A

hypersensitivity reaction

rash that covers entire body (puss filled marks) larger than smallpox

highly contagious

99
Q

The rash and symptoms from shyphillis resolve sponataneously and the patient enters the clinically ____ or ___ ____ where they belive they are cured?

A

inactive

latent phase

100
Q

___________ (Late ) Syphilis ______ years?

A small number of cases progress to this stage. Range of symptoms from mild to fatal infections

during this stage there is a relatively ____ number of bacteria?

A

Tertiary

3-30

low

101
Q

Tertiary Syphilis

in late stage syphilis the immune response is ____ _____ causing destruction of virtually any organ or tissue. Disabling fatigue, disfiguring skin leasions, bone malformation ( archeological information)

_

A

chronic inflammation

102
Q

fatal infectionsif vital systems/organs are affected cardiovascular and CNS.?

Complexes tht consist of ___ ______, _____ and host ______?

Depositied on various body sites and elicit and _____ _____ - ______ disease?

A

treponemal proteins

antibodies

inflammatory response

autoimmune

103
Q

Diagnosis and treatment of sypilis?

reliable _____ _____ have been available for decades?

A

bloods tests

104
Q

Diagnosis and treatment of syphilis

the _______ test is based on ____ produced by host not the bacterium!!!

______ is released from ______ ____ from lysing cells. not normally seeen by the immune system and processed as foreign (non-specific)

A

Wassermann Test

antigen

Cardiolipin

mitochondria membranes

105
Q

in the Wassermann Test a sample of _______ or ______ _____ is taken and introduced to the antigen.

But can be produced in response to other conditions, viral, protozoan, autoimmune diseases resulting in _______ ________?.

A

blood

cerebrospinal fluid

false positive

106
Q

there are now more sensitive test avaliable for T. Pallidum such as ____ test- _______ _______ test -(anti treponemal antibodies)

  • Based on the fact that the organisms lose _______ when incubated with serum containing anti-treponemal antibodies.
  • Both test require _____ ____ and _____ _____ (problem with sampling)
A

inactivation

Flurescent antibody test

motility

live organisms

sophisticated microscopes

107
Q

Because of expense, physicians use non-specific test such as _____ _____.

depending on the clinic or hospital

  • ______ ______ is used as preferred confirmatory test ( also resolves ____ _____)
  • but this is more sophisticated and problematic for ______ communities /contries?
A

Wassermann test

Western Blot

false positives

poorer

108
Q

Treatment

Syphilis is teated by ________, t. pallidum is one of the few bacterial species where _____ has not been observed?

But treatment must be administrated early to avoid damage caused by ______ disease triggered by the bacterial infection?

currently there is no _____ for syphilis?

A

Penicillin

resistance

autoimmune

vaccine

109
Q

Tuskegee Experiment

-one of the most outrageous abuses in medical history undertaken in ______, ______ by the ______ _____ ______ ______?

A

Tuskegee

Alabama

U.S. Public Health service

110
Q

Tuskegee Experiment

in ______ -____ poor rural black men who thought they were receiving free health care from the U.S. government.

INvestigators enrolled in the study of _____ improverished African American _______ from _____ _______, Alabama.

A

1930-1972

600

sharecroppers

Macon County Alabama

111
Q

Tuskegee Experiment

For participating in the study the men where given free ____ ___,____, and ____ ______?

of the 600 men ____ had previously contracted syphilis and ______ without the disease.

They were _____ _____ they had ______, nor were they ______ for it?

A

medical care

meals

free burial insurance

399

201

never

told

shyphilis

treated

112
Q

Tuskegee Experiment

The Experiment was a _____ year study that was controversial for reasons related to _______ ____; primarily because reasearchers ________ failed to _____ patients appropriately after the ______ validation of ______ as an effective cure for the disease they were studying?

A

40

ethical standards

knowingly

treat

1940’s

penicillin

113
Q

Tuskegee Experiment

By the year _____, penicillin had become the standard treatment for syphilis but the study continued.

The study continued under numerous Us public Health Service Supervisors until _______ when a leak to the press eventually resulted in its termination.

A

1947

1972

114
Q

Tuskegee Experiment

The victims of the study included numerous _____ who dies of syhillis, _____ who contracted the disease and ____ born with _____ ______?

A

men

women

children

congenital syphilis

115
Q

Tuskegee Experiment

cited as “arguably the most infamous biomedical research study in U.s. history, led to _____ ___ ____ for the protection of human subjects. Now studies require ____ ____( with exceptions possible for U.S. Federal agencies which can be kept secret by Execuctive ORder, Communication of diagnosis and accurate reporting of test results.

A

institional Review Boards

informed consent

116
Q

prevention of Syphilis

  • Some parts of the world have eradicated or almost eradicated this disease.
  • Controlled by ____ ____, contact of sexual parteners for _____ ( test used to be used to obtain a marrige liscens in the US.)

-

A

safe sex

treatment

117
Q
  • Although at one time couples needed to have a certified blood test for (VDRL) syphilis “ Pursuant to the Marriage Amendment Act of 2008, DC Law.

Effective September 11, _______ a ___ ____ is no longer a requirment to obtain a marriage license in the District of Columbia.

-Problem with prostitution among drug uses that causes a viscous cycle of infection.

_Legalizedbrotheles ect have improved this situation - robust debate.

A

2008

blood test

118
Q

famouse people with syphlis?

A
119
Q

94
Legalized brothel etc have improved this situation- robust debate
1. Safety of the men and women involved in the sex industry
- State licensed and controlled.
- Safe working environment rather than on the street where abuse can take place
2. Increased control of diseases
- the workers are use safe sex and screened on a regular basis for STDs
- and clients are also screened, at least on a visual basis
- But certain groups in society are vehemently opposed to this but these measures have
been shown to have positive outcomes in Europe.

A
120
Q

Syphilis

______ of the organisum on the site of ____ triggers massive ____ ____, blood vessle _____ , tissue ______ or ______?

A

Replication

entry

leukocyte infiltration

damage

necrosis

Chancre

121
Q

Syphilis

Most cases of primary and _______ syphilis are spontaneously resolved by the _______ ________?

A

secondary

adaptive system

122
Q

Syphlils

primary and Secondary shyplilis are spontaneously resolved by the adaptive system involving?

A
  • CD8+ cytotoxic T lymphocytes
  • cytokine production ( a-interferon, interleukins) as demonstrated by degraded treponemes are found in phagolysosome.
123
Q

in some cases the adaptive system cannot cleare the organisum and can produce to the ______ _____ that may last for years or_____?

A

tertiary stage

decades

124
Q

________ studies have shown that _ ______ is largely devoid of ______ -__________ proteins?

A

Ultrastructure

T. Pallidum

membrane

associated

125
Q

_________ -_________ proteins that are present may be involved in ______ and _____ of the host and may be the target of the _____ ____ response?

A

Membrane

associated

attachment

invasion

adaptive immune

126
Q

_______ ____ harvested from ______ that are less susceptible to _______?

This Suggested that subpopulations of _____ _____ account for these ___________?

A

Persistent treponems

rabbits

macrophages

antigenic variants

persisters

127
Q

orgins of Syphilis

many blame _________ and his crew for bringing syphilis to ____ in ______?

skeletons from archaeological sites in the United states and Ecuador ranging in age from ______ to ____ years?

A

Columbus ( europen sailors not used to seeing beautiful women half naked …. led to sexual liaison)

Europe

1492

400

6,000

128
Q

Syphilis orgins

Europe constantly at War _______ in particular could spread disease because of ________ ______ to diffrent countries?

Small cities of people often accompanied ________, ______ , _____ and brothels were prominet - rampant ______ rate?

A

soldiers

constant movements

armies

Taverns

Prostitutes

infection

french -blames naples

italians - the french

russians- polish

english -spanish

129
Q

Syphlils

orgins

European evidence, especially syphilitic lesions in skeletons from a _____ centery _____ _______?

Now many new findings in England and Europe show tell tale signs of syphilis _____ years before the ________ of _____?

A

14

english monastery

70

voyage

Columbus

130
Q

What is PBP’s called Tp47

recently discovered PBPs called Tp47

A

The binding of the beta lactam component of Penicillin to Tp47 results in
hydrolysis of the beta-lactam bond of the antibiotic resulting in the
production of several byproducts.
The thought is that these byproducts have a higher affinity for Tp47 than the
beta lactam itself. Thus as a consequence of Penicillin being broken
down, products are released which make it more difficult for the betalactamase
to bind the antibiotic and deactivate it.

131
Q

Treatment of syphlis

Penicillin is the treatment of choice for treating syphilis. According to the
Centers for Disease Control and Prevention (CDC).
Patients with known penicillin allergies should undergo penicillin allergy skin
testing and penicillin desensitization, if necessary.
The 2010 CDC STD treatment guidelines recommend desensitization in
penicillin-allergic pregnant women, followed by treatment with penicillin.
Treatment
Many pathogens are resistant to Penicillin- so why not T. pallidum?

A
132
Q

Genome sequencing of T. pallidum: 1998

1.138 Mbp, one of the smallest genomes identified.
• 1000 genes

A

• Does not have genes for making nucleotides, fatty acids, most amino acids and
enzyme cofactors
- no wonder it cannot be grown in the lab.
*Now this is known these compounds can now be added to
artificial media in new attempts to grow this organism. –to
date not very successful.

133
Q

genome sequincing 1998

Over 20 genes encoding outer surface lipoproteins.

  • proteins to punch holes in host cells
  • or attachment proteins to stick to mucous membranes
A

But these surface proteins may be subject to antigenic variation
and adopt a “stealth” strategy leading to “persistence”
113

134
Q

syphlis reviw

• syphilis ancient disease that as mutated to take advantage of human
behavior
• no animal reservoir

A

• however modern treatment (antibiotics) is relatively simple
•Therefore could, in theory be eradicated but……
…. Human behavior cannot be controlled but through
safe sex practices we may be able to reduce the incidence?

135
Q

case study

1996, Georgia. Initial outbreak.
However, from a few individuals, investigations led to over 200 infected young
adults.
1 yr before the outbreak

A

• 18 young white girls with two groups of young men
- One group white, second was African-American
- met for drug, alcohol and sexual activities
- met in public areas, back seat of cars etc
- sequential and simultaneous partners
• limited or no safe sex practices -16 pregnancies and 200 infected individuals.

136
Q

Mycobacterium tuberculosis and Tuberculosis

is also called?

A

the peoples plague

one of histories most feared killers

Tuberculosis or consumption- because it seemend to consume people from within.

137
Q

Mycobacterium tuberculosis

  • Aerobic, very slow growth 6-8 wks to form colonies
  • Gr. +ve type cell wall but Gram stain not useful
  • High content of mycolic acids (lipids 10% cell weight) –leads to term

“acid-fast” as a robust method of staining is used

A

Highly contagious, aerosol spread (talking, sneezing, coughing etc)

138
Q

• Multiplicity of infection

Salmonella: 10 million,

E.coli 0157:- >10,

M. tuberculosis - 3

A

divides itself every 16 to 20 hours
E. Coli -20 mins

139
Q

TB shap and morphology

Acid-fast staining produces
diagnostic ________?

A

red bacilli

140
Q

TB

Described in _________by _________.
-Aggressive surveillance and antibiotic treatment
But today ….. Asylums dismantled, care in the community?!
• Still one of the most infectious curable diseases –________% of adult
deaths
• Top_______ killer along with______ and _____
-synergistic with HIC x800 chance of contracting TB

A

1882

Koch

20

3

HIV

Malaria

141
Q

• Tuberculosis (TB) is one of the top 10 causes of death worldwide.
• 2016, 10.4 million people fell ill with TB, and 1.7 million died from the disease
• Seven countries account for 64% of the total, with India leading the count, followed by
Indonesia, China, Philippines, Pakistan, Nigeria, and South Africa.
• TB is a leading killer of HIV-positive people: in 2016, 40% of HIV deaths were due
to TB.

A

• Multidrug-resistant TB (MDR-TB) remains a public health crisis and a health
security threat. WHO estimates that there were 600 000 new cases with resistance
to rifampicin – the most effective first-line drug,
• An estimated 53 million lives were saved through TB diagnosis and treatment
between 2000 and 2016.
• Ending the TB epidemic by 2030 is among the health targets of the Sustainable
Development Goals.

142
Q

Orgian of TB

Evolved from a disease of _____ in ______-____ BC in ______

  • probably from the soil organism _ ______

Early Egyptian mummies (1000 BC), found with characteristic _______ _________but not evidence of ______ _______ but this was found
in more recent mummies (Ramses II) (400-1000BC)

A

cattle

8000

4000

herdsmen

M. bovis

bone malformations

lung damage

143
Q

Earliest Known Human TB Found In 9,000 Year-old Skeletons
submerged off the coast of Israel
Characteristic bone malformations

A
144
Q

TB

Symptoms:

-highly contagious, 3 organisms can cause
disease!

A

Fever, coughing, bloody sputum, weight loss, and malaise
• Progressive, irreversible lung destruction
• Bones, joints, liver, spleen, GI tract and brain.
• Fatal, progresses slowly (yrs), more rapid in AIDS, fatality is 80%

145
Q

Chlamydia trachomatis

  • Small Gr-ve short rods
  • no detactable peptidoglycan
  • Obligate intracellular pathogen
  • Many serovars ( strains) associated with specific disease
  • Reduced genome - size 1000 kbp (E. colie 4600)
  • Unusual 2 stage life cyle
A

• Chlamydia is an organism that has very specific requirements that allow
it to exist in the cervix, urethra, and fallopian tubes.
You can get chlamydia by having vaginal, anal, or oral sex with someone
who has chlamydia.
• Because of these specific requirements, chlamydia cannot live
outside the body,

146
Q
A
147
Q

• Cervical infection is the most common STD
• US -4 million cases –cost $2 billion
• Little public perception of this organism and the diseases it causes
• Trachoma –chronic disease (North and sub-Sahara Africa, Middle
East, Asia and South America).

A
  • *- Causes blindness to 6 million
  • 150 million in need of treatment
  • Leading cause of preventable blindness**
148
Q

Stigma
- STD-gonorrhea and syphilis associated with
underprivileged etc, but

A

chlamydial diseases found on college campuses and rich
neighborhoods -doesn’t differentiate!!

149
Q

chlamydia in women

  • Cervicitis - inflammation of the tissues of the cervix
  • Pelvic inflammatory disease (PID)
A

Endometritis -inflammation of the endometrium, the inner lining
of the uterus
• Ectopic pregnancy /Premature birth
190

150
Q
  • in some cases Pelvic pain, chronic or acute
  • Newborn eye or lung infection
A

Makes women much more susceptible to HIV,
-macrophages, and T-cells travel to genital area and are the target of
the HIV

151
Q

chlamidia

men

• Prostatitis - inflammation of the prostate gland.

Epididymitis (covering of the testis) -the epididymis becomes
inflamed
• Fluid discharge?

A
152
Q

chlamdia

both sexes

  • Urethritis
  • Infertility
  • Proctitis (rectal disease and bleeding)
  • Long term can lead arthritis
A
153
Q

Life cycle of Chlamydia:

transition between two distinct developmental forms

Elementary Body (EB) -a small, dense cell that is resistant to drying
and means of dispersal.
Non multiplying, infectious agent (outside host cell).

A

Reticulate Body (RB) –larger, less dense cell, vegetative form -
multiplies (2-3hrs).
Non-infectious, multiply inside host cells to form a large inoculum for
transmission.
Whole cycle takes only about 48hrs.

154
Q

Avoidance of cell lysis.

No PG that normally provides strength to the bacterium – but

high osmolarity of the interior of a human cell prevents cell lysis of
reticulate body

A
  • modified membrane structure to strength the cell
    results in the large number of Serovars that refers to distinct variations
    within a species of bacteria
155
Q

chlamydia

Membranes with proteins containing multiple disulfide cross-links
•Major outer membrane protein (MOMP)
•Polymorphic outer membrane protein (POMP)
•Large and small Cysteine-rich proteins (CRP)

A
156
Q

Reduced Genome size:

Minimum genome is the smallest number of genes needed to
encode functions of a free-living microbe

A

But still has a complex life-cycle.
•Energy parasite as it uses host ATP
•Lacks genes for amino acid biosynthesis but
•But contains genes for several energy-generating pathways –
glycolysis, pentose phosphate pathway and a partial TCA cycle
202

157
Q

Virulence Factors:

Problem – we can’t grow C. trachomatis in cell-free culture. 10
litres gives >200mg (E.coli, many grams)

A

Genetic manipulation models- held back
• Mice- different mice show different levels of infection

158
Q

Adherence and Invasion by EBs

EBs have a number of ways of entering the cell:

-normal phagocytosis
• endocytosis,
• pinocytosis

A
159
Q
  1. Phagocytosis (literally, cell-eating) is the process by which cells
    ingest large objects, such as bacteria.
A

The membrane folds around the object (Pseudopodia), and
the object is sealed off into a large vacuole known as a
phagosome.

160
Q

Pinocytosis- (liThis process is concerned with the uptake of solutes and single
molecules such as proteins?
Formation of small vacuoles.

A
161
Q

Endocytosis (receptor-mediated)
–material absorbed from the outside by engulfing it with their cell membrane.
It is used by all cells of the body because most substances important to them are
polar and consist of big molecules, and thus cannot pass through the
hydrophobic plasma membrane.
Substances absorbed across the membrane via association with
specific receptors and requires energy

A
162
Q

•EBs enter and form vesicles known as Endosomes (near neutral
pH) Endosomes containing one EB may fuse with other endosomes –
know as an Inclusion.

A

Endosome membrane lipids may come from Golgi membranes in
addition to RB proteins (Inc proteins).
Hence this membrane is a hybrid of host and bacterial lipids and
proteins and is important in the non-fusion withlysosome.

163
Q

• EBs are covered with projections which appear to penetrate the
endosomal membrane to reach into the cytoplasm.
• These projections appear to be hollow, transport of nutrients from cell
or introduce bacterial proteins into cytoplasm.
• EBs transformed into RB and begin to replicate (2-3 hrs-relatively rapid).
• As the number of RBs increase the endosome membrane expands to
accommodate these.

A

• For the endosome membrane lipids may come from Golgi
membranes in addition to RB proteins(Inc proteins).
• Hence this membrane is a hybrid of host and bacterial lipids and
proteins and is important in the non-fusion withlysosome.
• RBs stay attached to endosome membrane, but at some point
migrate to the internal part of the vacuole and differentiate into EBs.
212

164
Q

• During RB replication stage, even though the cells can take up a large
proportion of the host cell, little damage or adverse functionality
appears ?
Organism totally dependent on cell for nutrients and energy
214

A

•After about 40hr EB are release from cells
Actual mechanism is unknown and may be the result of 2 events:-
1. lysis of cells and release EBs into cytoplasm that can infect adjacent
cells.\
2. endosomal membrane can fuse with cell membrane releasing EBs and
RBs intocytoplasm or extracellular space to infect adjacent host cells.

165
Q

Active discussions / research on this on how damage is caused to host cells
Some scientists think, some host cells are killed during the process of EB escaping
the cell causing tissue damage
some think it is the immune response to EB that is thought to be the main cause
of cellular damage.

A

Inflammatory response could be to EB and other proteins prior to the EBs
entering the host cells or when released from the cell causing collateral damage.
Could be strain specific

166
Q

Lymphogranuloma venereum

• Caused by distinct serovars (strains) of C.trachomatis, and is the only
chlamydial infection that invades beyond the epithelial cell layer.

A

Affect both men and women,
1st stage1-4wks, primary lesion -penis, urethra, scrotum, vaginal wall,
cervix, vulva.
Absence of pain, but fever, chills, anorexia.
2nd stage –inflammation and swelling of lymph nodes- buboes

167
Q

Buboes -rupture- infection becomes systemic -fever, chills,
anorexia, headache.
• Bacteria spread to other regions, eg.rectum
Reifer’s syndrome (urethritis, conjunctivitis) or reactive arthritis
3 seemingly unrelated symptoms: arthritis, redness of the eyes, and
urinary tract signs….
….Although most chlamydia infection remains localized. When the
infection becomes systemic the bacteria can travel to joints and
other body parts –inflammation leads to pain.

A
168
Q

Prevention and Treatment:

In studying infection rates of chlamdyia among 800 army recruits, UK researchers
found that nearly 90% of those who tested positive for chlamydia showed no obvious
symptoms.
most men with chlamydia have no symptoms“Many studies have shown about one in 10 women are infected,

A

Both can be carriers but males tend not to be as quickly diagnosed and spread the
disease from partner to partner.
recommended screening for chlamydia in all sexually active females aged
24 years or younger and in older women who are at increased risk for
infection.

169
Q

Screening /treatment

• Historically, detection was a problem- invasive methods
- Women –cervical cell sample•

A

Men – urethral cells needed to be collected
–”urethral stripping” –small brush inserted in penile opening –
painful –locker room talk- discouraged men seeking medical aid!

170
Q

• Gram stain to eliminate N. gonorrhoeae from diagnosis –culturing is
time-consuming and expensive (Chlamydia is too small to view via a
microscope)

A

• Now **rapid diagnostic tests

  • DNA probes, PCR and other DNA amplification methods.
  • –specific monoclonal fluorescent antibody tests**

Non invasive / rapid tests used with urine sample

171
Q

chlamidia

no vaccine avalaoble

A

•Treatable with antibiotics, Chlamydia and N. gonorrhoeae.
- Doxycycline (a tetracycline) and azithromycin (macrolide) (inhibit
protein synthesis) +
- Cephalosporin (cell wall –PG) for gonorrhea.
•Resistance not a problem -yet?
Probably due to the organisms lifestyle, not in contact with other
bacteria or antibiotics when compared with gut microorganisms. (
reduced risk of Lateral gene transfer)
224

172
Q

The Chlamydial peptidoglycan paradox

Why is C. trachomatis susceptible to penicillin whose main mode of
action is to inhibit PG synthesis?

A

Small amounts produced that cannot be detected with current
methods?

173
Q

Development of EBs from RBs is affected
-division of RB is affected by Penicillin
- a number of Penicillin Binding Proteins are specifically affected
- these appear to be less accessible to penicillins in the Ebs and therefore
resistant to the antibiotic.

A

Pathogenomics - genomic studies have provided recent
information and confirmed the small genome..?
226

174
Q

Genome contains genes that appear to encode a near complete
pathway for synthesis of PG
Found in 5 species of Chlamydia confirming the conservation of this
pathway

A

Microarray analyses of transcription revealed a marked increase in
expression of PG synthesis genes at later developmental stage including
RB division.
1.8 % of genome composed of genes for PG and its been suggested
that PG plays an important, yet atypical role in chlamydial cell biology
so susceptible to Penicillin

175
Q

Final Thoughts:
• Very unusual organisms –once thought to be viruses due to very small size
• 6 species from many animals, specific strains may cause different symptoms
within the host
• Many interactions with host cells
• Much to be learned form these interactions
- Drug delivery systems
- other ways of destroying bacteria

A

•Developing countries -still causes blindness
• The most prevalent STD and in the US (4 M = 5%).
•Asymptomatic infections- Screening with new cheaper DNA methods
may facilitate early detection.
• Need to increase treatment of men who are the main carriers.
•Safe sex practices
230

176
Q

Case study: Outbreak of Lymphogranuloma vernerium in
Homosexual Men
2003 –Rotterdam the Netherlands, men aged 26-48.
• cluster of ulcerative STD, tests showed the same pathogen

A

•13 were HIV positive, 8 had additional STDs
•All reported unprotected sex !!
•Many anonymous relations -contact tracing difficult but traced to
individuals in Germany, Belgium, UK and France.

177
Q

Infectious Disease: The Future

• Need for alternative antimicrobial compounds (and appropriate
use of these?!)
• Genome sequencing will lead to:

  • better, more rapid diagnostic tests
  • the ability to grow bacteria that so far have eluded culture?
A

• Molecular tests will take precedence in the laboratory, but rapid diagnosis
through MALDI-TOF-MS is changeling molecular methods
• Globalization, transmission of microbial agents can be extremely rapid
• Gene therapy, and other new treatments –Bacteriophage therapy/ Viral
drug delivery systems, pre and pro-biotics will have a major impact on
future……
….will paralysis, blindness etc be treatable and eliminated !!!!

178
Q

• Will society become two-tiered?
- The rich and the poor, the have and have-nots
- Those that can afford health care and those that
cannot.

A

• will we squander the Earths’ resources? -oil?
- water and food sources could /are become limited!
- could be a potential target for terrorists
- limited resources could be the spark that ignites local
and global conflict

179
Q

The immune system in infants requires stimulating, lets not all use
disinfectant / antimicrobial compounds in wipes to try and sanitize all
things

A
  • We should not try and raise children in a sterile environment
  • Antibiotics should be cherished as a weapon against pathogens but
    must be used appropriately we may be in the twilight of there
    usefulness!
180
Q

TB.

Progression of the Disease:

  1. Entry of host – aerosols in airway.
  2. Invasion of unactivated alveolar macrophages: key factor
A

-stage process
M. tuberculosis binds directly to a macrophage surface proteins CR3
and CR4 (complement receptors).
Unactivated macrophages have fewer CR3 than CR4 but PMNs rushing
to infection site have more CR3. Inflammation also increases CR3
receptors.

181
Q

TB.

• T-helper (CD4+) stimulate antibodies against M.
tuberculosis but cannot act on intracellular organisms (serum
resistant).
but -M. tuberculosis also:-

A

• interferes with produce IFN-g that stimulates macrophage
activation
• Interferes with production of Cytotoxic Lymphocytes (T cells) cells
that kill infected phagocytes

182
Q

• Internalization of bacteria in a vesicle (not normal
phagocytosis) that appears to have a reduced ability to fuse
with lysosome by preventing acidification.
• Reduced oxidative / respirative burst

A

• Reduced ability to produce IL-12 (cytokine) that stimulates Th-
1 response – reduced antibody response?
• reducing antibodies may give the bacteria an advantage and
time for more to invade macrophages.

183
Q

TB

II. Some of the bacteria are killed, those that survive appear to bud-off
from the vesicle but still have a membrane encasing them.
Evidence:
MHC-I cytotoxic T cell response (antigens processed from an internal
source)……

A
184
Q

TB

MHC-I antigen presentation pathway –
All cells have MHC complexes for host recognition.
• Protein antigens degraded by the proteasome in the cytoplasm
are transported across the endoplamic reticulum membrane
formed by the TAP (transporters associated with antigen
processing).

A

• MHC-I protein is held in place by a chaperone until the peptide
is bound
• Chaperone is released and the protein complex is transported
to the cell surface and interacts with the T-cell receptors
(TCRs).

185
Q

TB

In addition other cells of the immune system are involved
B cells have antibodies that recognize a foreign antigens
The antigen is internalized and in turn presented to a T helper
cell that stimulated the B cell to differentiate into plasma cells
that produce more antibodies to search out mycobacteria.

A

Mycobacterium tuberculosis is able to overcome these
mechanisms ii that they actively infect macrophages and survive
the destructive activates normally found in the phagolysosome.

The T cell response is not initiated and so cytokines, IFN,
gamma TNF are not produced.
These normally recruit more macrophages to the site of
infection and increase phagocytosis and inflammation

186
Q

• if the phagocytes fail to kill the bacteria, T cells and
macrophages wall off growing bacteria with a thick fibrin coattubercle
- Granulomatous response.

• Calcification, visible on chest X-rays

• Phagocytes trying to kill bacteria cause considerable damage
to lung tissue –lysosomal enzymes, TNF-a.

A

• Lesions initially have a thick (cheeselike) consistency
(caseous necrosis)
• as phagocytes continue to enter site the necrotic region
becomes more liquid- easier to become aerosols
-more contagious
• Bacteria spread to other parts of the body

187
Q

TB

Latency and Persistence: TB can be a chronic infection

• bacteria in lungs (and other organs?) can persist for decades. If later in life
suppression of the immune system may allow these to break out and
multiply. Latency.
- Reactivation TB
• Persistence factors – allow bacteria to survive for long periods.
- genes found that are related to sporulation (spores) mechanisms
- Metabolic shutdown

A

Evidence for latency -Animal models:

• Mice develops TB similar to humans.
• Treated with anti-TB drugs, bacteria are cleared, but DNA is still
detected byPCR ?
• Gene coding for a-crystallin, a chaperone protein, expressed
during stationary phase. Disruption of this gene reduces
persistence.

188
Q

TB

Virulence Factors:
No toxins or hydrolytic enzymes !
• Research hindered by low generation time 18-24 hr. Takes weeks to form
a colony on agar.
• Molecular techniques were impeded, difficulty in extracting DNA

A

• Culture mammalian cell lines (macrophage like) now used to investigate
virulence factors.
So if no toxins or degradative enzymes how does the organism cause disease?
151

189
Q

TB

Induction of destructive Inflammatory response
Even though some M. tuberculosis cells escape the immune response
enough appear to persist and do initiate an immune response.
Experimental evidence…….

A

Cell wall components:
•Mycobacterium mycolic acids injected into animals elicit an
inflammatory response.
•PG-trigger production of
-Cytokine, TNF-a /macrophage toxic lysosomal components
Result - destructive lung tissue damage.
152

190
Q

Factors that affect host susceptibility and severity of
symptoms…
Different individuals in a population exposed to TB respond very
differently from:-
no infection — latent infection — active /chronic infection.

•Size of inoculum, length and number of exposures all have an
affect but…….

A

Are there genetic predispositions that render some
people more susceptible to infection?
Mouse models
Bcg - genetic locus involved in susceptibility of different strains of
mice to TB
Codes for natural resistance-associated macrophage protein

191
Q

TB

Diagnosis, Treatment and Control:

1800s Sanitariums, fresh-air: wide-open windows, outside
balconies (hot summers/freezing winters.
USA:
1900 – 34 Sanitaria
1925- 356 sanitaria
Not a cure -death rate still 69%
156

A

• Highly contagious
• Isolation in negative-pressure hepa-filtered room
• face masks with high efficiency filters.
But first you have to identify the disease and
individuals infected….

192
Q

TB

Early diagnosis difficult, asymptomatic patients, slow gradual progression
and symptoms may be slow to show themselves…..
Fever, chills, and night sweats.
Fatigue and weakness.
Loss of appetite and unexplained weight loss.
Shortness of breath and chest pain.
These can be general symptoms associated with a number of diseases
but…
158
….. not for more than 2 weeks becomes a cause for concern
A cough with thick, cloudy, and sometimes bloody mucus from the lungs (sputum).
Test for presence of “acid-fast” bacillus in sputum (but must be present in
larger numbers)

A
193
Q

Tuberculin test.
Tuberculin, protein extracted from M. tuberculosis is injected and a
localized immune reaction is seen.
Pre-primed TH CD4 cells at the site of injection secrete cytokines.
Poly Mono Nucleocytes (PMNs), monocytes and macrophages are
recruited to the injection site leading to the immune reaction…

A

Positive test: Redness and swelling -48-72 hrs
Demonstrates prior exposure to the bacterium 159

194
Q

Problems:

with TB skin test

A

Takes 4 wks after exposure, so recent infections are missed.
Many people show this trait showing past exposure (low level as
soil organism) or vaccination by BCG.
False positives / cross-reactivity to other species of
Mycobacterium.

195
Q

Search for better tests:
Bypass the need to culture this slow growing organism.
• PCR and sequencing - Extremely rapid (hrs):-
-16S rRNA genes but low copy number therefore other targets
favored
• Probes to Insertion elements (in other regions of the chromosome)
that are specific to M.tuberculosis strains.
• Interferon Gamma Release Assay (IGRA)

A

Interferon Gamma Release Assay (IGRA)

Prior BCG (bacille Calmette-Guérin) vaccination
does not cause a false-positive IGRA test result.
White blood cells from most persons infected with M.
tuberculosis will release interferon-gamma (IFN-g) when mixed with
antigens (substances that can produce an immune response) derived
from M. tuberculosis.

196
Q

TB

Antibiotics and the1939-Selman Waksman and his graduate students (Albert Schatz)
started screening soil organisms for anti infectious disease
properties.
1945 -clinical use of Streptomycin derived from actinobacterium
Streptomyces griseus
1952, Waksman received Noble Prize but not Schatz who did most of
the work and development. problem of resistance

A

Inhibits the synthesis of the waxy cell-wall and so
susceptible to macrophages and the phagolysosome process

-• Special antibiotics used- Isoniazid (inhibits mycolic acid synthesis)
• Rifampin (inhibits processing of RNA and shuts down protein
synthesis)
Basic lack of knowledge on how anti-TB drugs work

197
Q

TB

Drug cocktail developed –MDT (Multiple-drug-therapy)
Rifampin and Isoniazid

A

Used for 9mths but shown that patients were not completing
the course of drugs

Late 1980s: CDC –Direct Observation of therapy (DOT)
Drug cocktail developed –MDT (Multiple-drug-therapy)

198
Q

Resistance:
• Isoniazid-rifampin –most effective combination 90%
• But resistance occurs at high frequency – 50% mortality
• If so effective (ideal conditions), why resistance so high?
• Slow growing, long treatment times -9-12mths, patients didn’t finish the drug
program 10% (early programs had officials to ensure compliance) –DOTS helping
this.

A

Is the worst yet to come?
1. MDR-TB –Multiple Drug Resistant TB.
• Resistant to 2 or more of anti-TB drugs (isoniazid and rifampin)
• 1990s W strain emerged in New York, resistant to almost all of the
antibiotics used.
• Highly virulent and infectious
• Could have gone out of control- drastic measures
-isolation
-surgical removal of lung tissue
-use of experimental drugs
74% mortality
169

199
Q
  1. XDR-TB –Extremely Drug Resistant TB.
    • defined as resistant to isonizid and rifampin and at least 3
    second line drugs
    These strains are a major problem and are predicted to kill millions
A
  1. Extensively Drug Resistant tuberculosis (EDR-TB), !!

New deadly strain discovered
in India
Totally Drug Resistance

200
Q

Immunity and TB:
• Major killer worldwide- vaccine is a high priority

1930s work began

A

• Avirulent M. bovis strain BCG (Bacillus Calmette–Guérin) used as
vaccine. French scientists transferred for 231 generations over 13
yrs to produce this “Attenuated “ (weaken strain).
• Enters macrophages, breaks down eliciting an immune response
but does not cause disease
• Easily administered -orally and can be given to infants

201
Q

TB

• first used on Germany, 1930 but not a good start
- 249 babies, 79 died!
- not from BCG vaccine but from contamination from live
M. tuberculosis stored in the same incubator!!
- restricted the use for decades because of public
concerns.
173

A

Not all plain sailing:
• Does not prevent reactivation
• Protective range - 0 to 80% - so extremely variable between
populations!
- Genetic predisposition of human populations
- make all patients skin test positive ?
• BCG elicits different immunogenic properties to
M. tuberculosis.
• Recent discovery of bacteriophages that convert avirulent
vaccine strains topotential deadly pathogen!

202
Q

Future vaccines
• Introduce M. tuberculosis genes into BCG vaccine.
- Introduce genes for effective antigens from a number of
bacterial species for a multipurpose vaccine effective against a
number of diseases.
Requires a live vaccine that replicates briefly in the body to establish
immunity.
Use of psoralen and UV treatment, cross-links DNA and prevents
DNA synthesis while allowing protein synthesis and
metabolism. Organisms do not multiply but remain alive and
produce antigens to illicit an immune response 175

A

176
Tuberculosis vaccine development
To reach the new End TB goals of a 95% reduction in TB deaths and a 90%
reduction in TB cases by 2035, a comprehensive approach is needed that
includes new and more effective vaccines
Bacille Calmette-Guérin (BCG) vaccine was developed in 1921 and remains
the only available vaccine against TB. Unfortunately, BCG is only partially
effective
Sixteen different TB vaccine candidates are currently in clinical trials.
These vaccine candidates include five which are based on whole cell
mycobacteria, and the remainder are various sub-unit based approaches in
which Mtb antigens are expressed as recombinant proteins recombinant
viral vectors.

203
Q

The Future: TB
Trials for “booster” vaccines -?
Problem with accessing success –many decades
Infant vaccines, shorter time period but still accessed in years
Discovery of new antigens not expressed in BCG
Latency –post-exposure multiphase vaccine would be important
to reduce incidence –not yet available
177

A

A return to old therapies?!

DOTS: Direct Observational Therapy Short course.
• adopted by WHO in 1992 to combat noncompliance
and complacency.
• health care workers physically watch patients swallow
their daily dose of anti-TB drugs. –back to the old days!
- within first 2- 4 wks patients become
noninfectious.
VERY EFFECTIVE:
Bangladesh, 85% cure rate, Peru, 90% cure rate.

204
Q

Mycobacterium and TB: Final thoughts
TB as killed million in the past and is the leading cause of death
from a curable infectious disease (30 million deaths over the next
decade)
In resource-poor countries and those blighted with HIV TB is on the
rise (1 person infected every second!!)
Largely forgotten in the USA
Almost 125 years after the discovery of the cause of TB it is still
“The Peoples Plague” and a scourge of mankind

A

patho exam 4 (3 decks)

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