Exam 2 - Week 1

Question 1

Describe gross/histological organization of thymus. Differentiate between the 3 parts and their individual function
- what type of selection in each part?

• *where do T cells vs B cells develop
• *Does thymus have lymphatic drainage? Why?

Answer 1

1. Cortex; positive selection (some negative selection as well)
   - outermost region of a thymic lobule (naive T cells)
2. Medulla; mainly negative selection
   - innermost region of a thymic lobules (mature T cells and HASSALL’S corpuscle)
3. Junction region (cortico-medullary junction); where immature T cells enter the organ. Mature cells leave via vasculature. (Thymus is a primary lymphoid organ so no lymphatic drainage)

**
A. T cells born in bone marrow but develop in THYMUS (primary lymphoid organ)
B. B cells develop in BONE MARROW (both primary and secondary lymphoid organ)

Question 2

Identify the following processes

1. • education of T cells to recognize non-self and ignore self
   • occurs DURING DEVELOPMENT of the host
2. • occurs THROUGHOUT the LIFE of the host

Answer 2

1. Central thymic tolerance induction
   - TCR that posses low affinity for self-MHC are positively selected to further differentiate and function in adaptive immunity
   - the T cells that posses useless TCR die by neglect
2. Peripheral tolerance induction
   - some self-reactive cells do escape the thymus. (This is why you need a second system called peripheral/secondary tolerance)
   - T cells become ANERGIZED here (in absence of co-stimulation)
   * *Autoimmune reactions can still occur tho (third party stimulation?)

Question 3

What is immunologic tolerance and what is the goal?

**what happens if these TCR/BCR recognize self?

Answer 3

• occurs during development to educate T and B cells to recognize epitopes derived from foreign pathogens and ignore those derived from self tissue
• the GOAL is that only T and B cells that have TCR and BCR that can bind to epitope of pathogen (MHC:peptide) should POPULATE THE PHERIPHERAL TISSUE
• The T and B cells that have TCR and BCR that recognize self will be excluded/deleted during development so as to allow non-self reactive cells to POPULATE SECONDARY LYMPHOID TISSUE AND ORGANS (spleen and lymph nodes)

Question 4

The case where self is recognized is defined as an abnormal immune response against self tissue and organs mediated by T cells and antibody produced by B cells

• *what is this process called
• give some examples (6)
  1) antibodies against joint tissue
  2) immune system attack gut epithelium
  3) immune system attack myelin sheath
  4) attack beta cells producing insulin
  5) T cells in skin cause formation of plaques
  6) antibodies against thyroid cause hyperthyroidism

Answer 4

AUTOIMMUNITY; 80 different autoimmune diseases

1) Rheumatoid arthritis
2) IBD (inflammatory bowel disease)
3) Multiple sclerosis
4) Type 1 diabetes
5) Psoriasis
6) Graves’ disease
* *both CD4 and CD8 T cells can be affected and cause these problems

Question 5

1. What is the unique feature of thymus?

• found in THYMIC MEDULLA
• concentric arrangement of reticular epithelial cells
• secrete a cytokine called TSLP
• In vitro, they direct the maturation of dendritic cells and aid in DC generation of Tregs

2. What happens to the thymus with age? Can new T cell precursors be generated?

Answer 5

1. HASSALL’S CORPUSCLE
2. A. HASSALL’S corpuscle
   - STructures increase with age and may have a role in development of auto-immune disorders
   - In vitro, they direct the maturation of dendritic cells and aid in DC generation of Tregs (with age, the more antigens you get exposed to, the more Tregs you need)

B. Thymus

• reduce in size (involutes) with age
• when thymus involutes, it develops adipose tissue but retains islands of thymic tissue which can continue to make T cell precursors if needed

Question 6

1. DESCRIBE THE DIFFERENT CELLS in the thymus responsible for antigen presentation (5)
   - which are derived in thymus vs bone marrow
2. What are cortical/medullary APCs

Answer 6

1. Cortical epithelial cell
   - thymic origin
2. Thymocytes (naive T cells start undergoing differentiation when they enter the thymus)
   - bone marrow origin
3. Medullary epithelial cell
   - thymic origin
4. Dendritic cell
   - bone marrow origin
5. Macrophage
   - bone marrow origin
6. 1 and 2 are in cortex, 3,4 and 5 in medulla
   - Cortex is dense with immature T cells
   - medulla is pale with mature T cells and Hassall corpuscles containing epithelial reticular cells

Question 7

1. What is the origin of thymic precursors
2. What proteins turns on T cell differentiation in thymus by transcription of genes?
3. How do the different T cells arise (alpha-beta, gamma-delta, CD4, CD8)
4. When do gamma-delta T cells arise ? Where do gamma-delta T cells function ?
5. Summarize early development of alpha-beta T cells in the thymus

Answer 7

1. Bone marrow
2. NOTCH
   - Notch protein cleavage of intracellular domain results in transcription of genes leading to T cell differentiation

3. 
A. A common DOUBLE NEGATIVE T cell progenitor gives rise to alpha-beta and gamma-delta T cells (in cortex) 
B. Uncommitted DOUBLE POSITIVE thymocyte - express both CD4 and CD8. **Once in medulla junction, you encounter negative selection. If they bind to class I, you lose CD4, if you bind to class II, you lose CD8 
**Double Negative (DN) cortical thymocytes express alpha-beta TCR and only later express CD4 and CD8 to become double positive thymocytes 

4. Gamma-delta T cells develop early in embryogenesis before many alpha-beta T cells and migrate preferentially to respiratory organs, skin and peritoneal cavity
   - they have a VDJ set of genes that is more limited in recognition of pathogen compared to alpha-beta
   - they respond more quickly that alpha-beta but do not generate memory
5. Progenitor cells originate in bone marrow - proliferate and travel to cortex - become double negative T cells which then commit to T lineage - rearrange beta genes (CHECKPOINT FOR PRE-TCR) - proliferating double negative pre-T cells become immature double positive cells - rearrange alpha genes (CHECKPOINT FOR PRE-TCR) - mature double positive cells (express CD4 and CD8)

Question 8

Differentiate positive vs negative selection

- where do they occur ? Why?

Answer 8

1. Positive selection; simply select what will bind to MHC (MHC:peptide)
   - Thymic CORTEX; (Double + Tcells CD4/CD8), epithelial cells present here
   - if T cell does not bind ; APOPTOSIS
   - T cells expressing TCRs capable of BINDING SELF-MHC on cortical epithelial cells SURVIVE.
2. Negative selection; select what will bind with low affinity to MHC
   - Thymic MEDULLA.
   - if class I bound; CD8 retained, CD4 lost
   - if class II bound; CD4 retained, CD8 lost
   - T cells expressing TCRs with high afinity for self antigens undergo APOPTOSIS.
   - T cells with low affinity binding of TCR to MHC:peptide will SURVIVE (seeds peripheral lymphoid organs)

Question 9

Identify

• transcription factor that can reduce the number of self-reactive T cells that escape the thymus
• allows for expression of several hundred tissue specific genes to be expressed by subpopulation of thymic epithelial cells allowing T cells to become tolerant of antigens that are expressed in the periphery - called tissue specific antigens (TSA)

How?
Expressed where?

Answer 9

AIRE (Autoimmuen regulator)

• Tissue-restricted self-antigens (TSA) are expressed in the thymus due to the action of autoimmune
  regulator (AIRE)
  • Expressed in THYMIC MEDULLA - you get both thymic and other antigens found out in the periphery
  • Children that lack the AIRE gene get disease get APECED Autoimmune polyendocrinopathy-candidiasis-ectodermal dystropy. (a lot of antigens left in periphery that cause damage)

**example is insulin secreted by beta cells is presented to T cells

Question 10

1. How are self-MHC class I and II proteins expressed in thymic APCs
2. Where does the peptide come from?

Answer 10

1. APCS are DCs, macrophages and other cells in thymus that do negative selection of alpha-beta T cells
   - pathogens are destroyed by CTL, cytokines and antibodies
2. Antigen provides peptides for thymic epithelial cells and medullary DCs
   - protein molecules expressed by cells in the thymus; APCs and debris from thymic microenvironment.
   * *remember, no lymphatic fluid enter (Thymus is a primary lymphoid organ)

Question 11

How is response to self controlled in the periphery

Aka If self reactive T cells escape the thymus, How are they controlled

Answer 11

• Thymus does not expressed every antigen found in body. The peptides are derived from proteins in thymus. So MHC:peptide is restricted to thymus (AIRE helps with antigen in periphery to be resented in thymus)

• you should eliminate all self- reactive T cells in thymus by central thymic tolerance
• however, some self reactive T cells get out into the periphery which can be anergic if there is no costimulation (peripheral tolerance)
• but why still have problem? Third party stimulation

• Self - reactive T Cells in periphery die cause of no stimulation. There is however a third party stimulation
- one way it could occur is during response to pathogen ; if chronic inflammation occurs, uptake and continues presentation of pathogen peptides could lead to mistakes - normal peptides could be presented along with costimulatory molecule expression

Question 12

Match the follwoing thymocyte location and characteristics with the stage in development ]

1. Double negative CD3- (no CD4 or CD8) thymocytes in the SUB CAPSULAR ZONE of thymic cortex
2. Double positive CD3+ (have both CD4 and CD8) thymocytes in the THYMIC CORTEX
3. Double positive CD3+ thymocytes throughout CORTEX and especially at the CORTICO-MEDULLARY JUNCTION
4. Mature self-restricted, self-tolerant, single-positive CD4 or CD8 T cells leave the thymus in BLOOD VENULE

Answer 12

1. Proliferation and differentiation to double-positive CD3+ thymocytes
2. Positive selection (select T cells that bind self MHC)
3. Negative selection (select T cells with low affinity binding to MHC)
4. Entry to the circulation
   - they are single positive here; either CD4 MHC class II:peptide or CD8 MHC class I:peptide

Question 13

Differentiate the following

1.

• double + T cells (CD4/CD8)
• epithelial cells present
• self class I or II + peptide
• if T cell does not bind lead to apoptosis
• if T cell binds to self MHC signal ; T cell survives

2. • if class I bound; CD8 retained and CD4 lost (vice versa)
   • T cell has high affinity binding; apoptosis
   • T cell has low affinity binding; T cell survives
   • seeds peripheral lymphoid organs

Answer 13

1. Positive selection

2. Negative selection

Question 14

Identify definition

1. breakdown of mechanism responsible for self tolerance and induction of an immune response against components of the self
2. specific immunological non-reactivity to an antigen
   resulting from a previous exposure to the same antigen.

Answer 14

1. AUTOIMMUNITY
   - such an immune response may not always be harmful (e.g anti-idiotype antibodies)
   - however, in numerous autoimmune diseases, it is well recognized that products of the immune system cause damage to the self
2. TOLERANCE
   - The most important form of tolerance is non-reactivity to self antigens
   - we normally do not mount a strong immune response against our own self antigens - called self tolerance
   - autoimmune disease develops when the immune system recognizes a self antigen and mounts a strong response against it

Question 15

What are the 2 main causes of autoimmune disease

Answer 15

1. Genetic factors
   - inherited risk for most autoimmune diseases can be attributed to MULTIPLE LOCI
   - several diseases linked to particular MHC ALLELES (faulty negative selection) **HLA B27 - ankylosing spondylitis
   - polymorphism in non-HLA genes (contribute to failure of self tolerance and/or abnormal activation of lymphocytes)
2. Environmental factors
   - infections
   - medications
   - stress
   - diet
   - chemicals
   - hormones

**Others; modification of peptides by deamination or citrullination, smoking, HLA allotypes **HLA B27, age related thymic involutes next, identical twin with autoimmune disease

Question 16

Identify the hypersensitivity types (according to allergy, transplantation or autoimmunity) **Dont look - state all

1. Allergy only (no transplantation or autoimmunity issues)
2. Allergy - chronic urticaria
   Transplant - hyperactive rejection
   Autoimmunity - autoimmune hemolytic anemia
3. Allergy - serum sickness
   Transplant - chronic rejection
   Autoimmunity - SLE (systemic lupus erythematosus)
4. Allergy - poison ivy
   Transplant - acute rejection
   Autoimmunity - Type 1 diabetes

Answer 16

1. Type I
   - aka immediate hypersensitivity
   - rapid and occur within minutes of exposure to an antigen (involve IgE)
2. Type II
   - initiated by binding or antibody to cell membrane or ECM (antibody mediated)
3. Type III
   - interaction of antibodies with soluble molecules (immune complex)
4. Type IV
   - delayed (cell-mediated)

Question 17

The following MHC alleles are associated with what autoimmune diseases?

1. ***HLA - B27
2. HLA-DRB 1*01/04/10
3. HLA-DRB1*0301/0401
4. HLA-DR4

Answer 17

1. ANKYLOSING spondylitis
2. Rheumatoid arthritis
3. Type 1 DM
4. Pemphigus vulgaris

Question 18

Identify 3 mechanisms by which microbes may promote autoimmunity

Answer 18

A. Self tolerance ; T cells destroyed by deletion or anergic and don’t respond to stimuli

B. Induction of costimulators on APCs - autoimmunity

C. Molecular mimicry; self reactive T cell that recognize microbial peptide which lead to activation of T cells lead to autoimmunity

Question 19

1. Identify thee autoimmune disease

• POSTER CHILD OF AUTOIMMUNE DISEASE
• Smoking increases risk
• Cytokines affected (IL1, IL6, IL7 and TNF alpha)

2. Identify pathophysiology
3. Identify presentation (S&S)

Answer 19

1. Rheumatoid Arthritis
   - can occur in response to an antigenic trigger such as an infection
   - genetic factors play a role (HLA-CRB1*0401)
   * *20% of patients don’t have this antibody so you can’t rule out RA based on genetic testing
2. Pathophys
   - pathologic changes start in the synovial lining w/ neovascularization and thickening of synovial membrane
   - synovial proliferation - pannus formation (acts like local tumor)
   - pro-inflammatory cytokines affected
3. Presentation
   - stiff in the morning, inflammatory arthritics, rheumatoid nodules (elbows), eye disease (synovial fluid), serologic abnormalities

Question 20

Identify autoimmune disease

• elevated blood sugar based on low or no insulin
• Eye disease (retinopathy), neuropathy, vasculopathy, insulin dependent
• Presentation; attack B cells in pancreases - destruction of islet cells - no clinical symptoms for a long time

Answer 20

TYPE 1 DM

• one or more environmental triggering events - subclinical beta cell dysfunction - clinical type 1 DM developed
  (Takes a long time of insulin deficiency before you show symptoms of Type 1)

Question 21

Identify the following autoimmune diseases

1. Sensory symptoms in limbs, visual symptoms, motor symptoms, diplopia, gait problems, pain
   Brain MRI*
2. Ocular symptoms, dysarthria, dysphasia, respiratory involvement
   * antibodies attacked

Answer 21

1. Multiple sclerosis

2. Myasthernia Gravis

Question 22

Identify autoimmune disease

• BUTTERFLY RASH - malar rash (sparing of labia folds - mouth)
• Mainly in females (funmilola)
• Systemic disease
• AUTOANTIBODIES
• SYMPTOMS; butterfly rash, joint pain, serosal memebranes, kidneys (BAD case), CNS (not common but life threatening), lungs, heart, hematopoietic system

Answer 22

SLE

Systemic lupus erythematosus

Question 23

Identify autoimmune diseases

1. • hyperstimulation of thyroid glands
   • Excess metabolism; weight loss, diarrhea, anxiety, eye disease
2. • fatigue, constipation, skin involvement, muscle weakness
   - can have symptoms of hyperthyroidism when thyroid is stimulation and hypothyroidism when thyroid is not stimulated
   • Lymphocytic infiltrates

Answer 23

1. Graves’ disease
   ptosis- graves ophthalmopathy
2. Hashimoto’s thyroiditis

Question 24

Identify 4 therapies you can use for autoimmune disease

Answer 24

1. Steroids; Prednisone, Methylprednisolone, Dexamethasone
2. Immunosuppressant; Azathioprine, Cyclophosphamide
3. Antimetabolites (methotrexate, leflunomide)
4. Targeted biological therapies; target cytokines to inhibit them

Question 25

Define

• conditions characterized by intrinsic deficits within the immune system and are caused by inherited or de novo genetic defects

Give examples

1. B cell disorders (3)
2. T cell disorder (1)
3. B and T cell disorder (4)
4. Phagocyte dysfunction (2)

Answer 25

PRIMARY IMMUNODEFICIENCY DISEASES

1. B cell disorder
   - X linked (Bruton) agammaglobulinemia (all Ig low)
   - Selective IgA deficiency (only IgA low)
   - common variable Immunodeficiency (low Ig and plasma cells)
2. T cell
   - Thymic aplasia (Digeorge syndrome); low calcium, PTH and T cells, no thymic shadow
3. B and T cell disorder
   - SCID; no thymic shadow or T cells or germinal centers
   - ataxia-telangiectasia (high AFP but low IgG,A,E)
   - hyper IgM syndrome (normal or high IgM, vey low IgG,A,E)
   - Wiskott-Aldrich syndrome (low to normal IgG,M but increased IgE,A, few platelets)
4. Phagocyte dysfunction
   - leukocyte adhesion deficiency type 1 (increased neutrophils in blood but absence of neutrophil in target site - NO PUS)
   - CGD chronic granulomas disease (increase susceptibility to catalase + organisms)

Question 26

Identify 3 symptoms of immunodeficiency

Answer 26

1. Infections
   - frequent, severe, unusual organisms, difficult to treat
   - failure to thrive
2. Autoimmune disease
   - immune system no longer able to properly distinguish self from non-self
3. Immune dysregulation
   - impaired tumor surveillance
   - hematopoietic malignancy

Question 27

Identify the following CD (cluster of differentiation) antigens

1. All T cells
2. Helper T cells
3. Cytotoxic T cells
4. naive T cells **
5. Memory T cells **
6. B cells
7. NK cells

Answer 27

1. CD3-all T cells (double negative)
2. CD3+/CD4+-”Helper” T cells
3. CD3+/CD8+-Cytotoxic T cells
4. CD3+CD45RA+–Naïve T cells
5. CD3+CD45RO+–Memory T cells
6. CD19 or CD20—B cells
7. CD16+ CD56+–NK cells

Question 28

Immune system - simplified

Identify cell types under the following category

1. Cellular innate
2. Cellular adaptive
3. Humoral innate
4. Humoral adaptive

Answer 28

1. Phagocytic cells (NK cells)
2. T cells
3. Complement, antimicrobial peptides
4. B cells

Question 29

Identify the following primary immunodeficiency

Type - PHAGOCYTE DEFECT
- CATALASE POSITIVE (increased susceptibility to catalase positive organisms)
• Mostly in childhood but few exceptions in adults
• Weird bugs in normal places or normal bugs in weird places (recurrent bacterial and fungal infections)
• Beyond 2-4 weeks (wound healing is poor) and LACK OF PUS
• You can get TB (mycobacteria) from BCG vaccine

A. Defect ?
B. Findings? (what test do you order to test ability of polymorphonuclear cells PMNs to generate an oxidative burst -2)
C. Treatment (3)

Answer 29

CGD - Chronic Granulomatous Disease
*15months male w/ resp distress, CXR white out on right (thought it was pleural effusion), Abx didn’t work , CT showed abcess, bronch lavage showed hyphae in alveolar fluid

A. Defect;

• defect of NADPH oxidase - low ROS (superoxide) and low respiratory burst in neutrophils
• X linked form is most common

B. Finding

• DHR test (dihydrorhodamine) show low/no green fluorescence
• Nitroblue tetrazolium test fails to turn blue

C. Treatment

• prophylactic abx
• gamma interferon
• bone marrow transplant

Question 30

Identify the following primary immunodeficiency

Type - PHAGOCYTE DEFECT

• 6 wk old female infant w/umbilical stump still in place (red, inflammed, not healing, no purulent drainage)
• treat with prophylactic abx and bone marrow transplantation

**Identify defect, presentation, findings

Answer 30

LEUKOCYTE ADHESION DEFICIENCY (TYPE 1)

A. Defect

• defect in LFA-1 INTEGRINS protein on phagocyte; impaired migration and chemotaxis
• AUTOSOMAL RECESSIVE

B. Presentation

• recurrent skin and mucosal bacterial infections
• NO PUS and impaired wound healing
• delayed separation of umbilical cord (over 30 days)

C. Findings

• HIGH neutrophils in BLOOD
• absence/no neutrophils at target site

Question 31

The following are specific diagnoses of what primary autoimmune defect?

1. CGD (chronic granulomatous disease)
   - X linked or autosomal recessive
   - leukocyte adhesion deficiency
   - Chediak-Higashi syndrome
   - Neutrophil specific granule deficiency
   - congenital agranulocytosis

Answer 31

PHAGOCYTE DEFECTS (cellular innate)

Question 32

Identify the primary immunodeficiency

• primarily characterized by severe, recurrent or atypical infections with HERPES VIRUS

Answer 32

NATURAL KILLER CELL DEFICIENCIES (cellular innate)

- can occur due to quantitative of functional NK cell deficiency

Question 33

Identify the primary immunodeficiency

• 15 y.o male with fever, altered mental status and petechial rash
• labs; culture and gram stain of CSF=N.meningitidis, CH50=0, C6 deficiency

**what is the difference btw initial vs advances work up?

Answer 33

COMPLEMENT COMPONENT DEFICIENCY (humoral innate)

• present at any age depending on particular defect
• Early defects (C2, C4); sinopulmonary infections, autoimmune disease like SLE frequent
• late (C5-C9); increased susceptibility of NEISSERIAL INFECTIONS
• C3 defects are RARE; presents early in life
• *Initial; CH50(classical pathway) is generally zero. **if more than one complement protein is low/absent, suspect complement consumption
• *Advanced; AH50 (alternative pathway)

Question 34

Identify

• group of secreted pattern recognition receptors (PRRs) that are important in the protection of the skin and mucosal membranes and in the killing of phagocytosed organisms.

• Examples: defensins, cathelicidins,
bacterial permeability-increasing protein
(BPI)

Answer 34

AMPs (Antimicrobial peptides)

Question 35

Identify the following primary immunodeficiency

Type - Antibody deficiency

• 2 y.o BOY with freq ear infections, 3 episodes pneumonia, one bacteria meningitis, one pneumococcal sepsis
• labs; IgG low, IgA low, IgM low, protein based titer low ( diptheria, tetanus), polysaccharide based titer low (pneumococcus)
• CELLUALR IMMUNITY NORMAL
• CD19+ B cell deficiency

Answer 35

X-LINKED AGAMMAGLOBULINEMIA/XLA OR BRUTON’S AGAMMAGLOBULINEMIA (humoral adaptive)

• Absent B cells in peripheral blood
• increased in boys (approx 50% positive family history)
• NORMAL T CELL number and function

Question 36

Identify the primary immunodeficiency

• 30 y.o FEMALE
• required sinus surgery and needs abx 6 times a year for recurrent sinusitis. 3rd episode of pneumonia
• labs; IgG VERY low, IgA low, IgM low, titers low,
• CELLULAR IMMUNITY NORMAL

Answer 36

COMMON VARIABLE IMMUNODEFICIENCY (antibody deficiency)

• 90% or patients have no family history of affected family members
• significantly low IgG
• poor or absent response to immunization

Question 37

Identify the primary immunodeficiency

• 6 months old MALE, chronic diarrhea, cough diagnosed with PJP pneumonia
• lab; IgG low, IgA low, IgM HIGH, no protein based titers
  CELLULAR IMMUNITY NORMAL

Answer 37

HYPER IgM (B and T cell defect)

Defect; defective CD40L on Th cells - class switching defect 
- X-LINKED RECESSIVE (boys)

Presentation; early pyrogenic infection early in life, opportunistic infection with pneumocystis, CMV liver disease
*failure to make germinal center

Question 38

Identify the primary immunodeficiency

• 8 y.o female, positive celiac disease history, anaphylaxis with blood transfusion
• labs; IgG normal, IgA LOW, IgM normal, titers normal
• CELLULAR IMMUNITY NORMAL

Answer 38

SELECTIVE IgA deficiency (B cell disorder)

Question 39

The follwoing are under what class of primary immunodeficiency

• Agammaglobulinemia; X-linked, Autosomal Recessive
  • Hyper IgM Syndrome (HIGM); X-linked (lack of T cell help), Autosomal Recessive
  • Common Variable Immunodeficiency (CVID)
  • IgG Subclass Deficiency
  • Specific Antibody Deficiency
  • Selective IgA deficiency
  • Transient Hypogammaglobulinemia of Infancy

Answer 39

ANTIBODY DEFICIENCIES

Question 40

IDENTIFY primary immunodeficiency

• 5 mo old with chronic cough Dx with pneumonia twice by age 5
• intermittent colic, Messi, Chronic diarrhea and FTT
  Lab; IgG low, IgA low (normal for age), IgM low,
  ABSOLUTE LYPMHOCYTE COUNT LOW
• *identify 2 lymphocyte phenotypes do disease types
• 2 present in B cell but absent in NK cell or T cell

Answer 40

SCID - SEVERE COMBINED IMMUNODEFICIENCY (B and T cell defect)

• live in sterile environment (need stem cell transplant)
• X linked most common

2. Phenotypes (B cell only SCID)
   A. Common gamma chain deficiency (X-linked)
   B. JAK3

Question 41

Identify primary immunodeficiency

• 4 hour old infant
• seizure in nursery (low ionized calcium), heart murmur, visible cleft palate, lack or thymic shadow on CXR
• lab; IgG normal, IgA low, IgM low, total CD3 low, 0% naive cells and 100% memory cells, normal NK cells and B cells

Answer 41

DIGEORGE SYNDROME (22q11.2 deletion syndrome)

• T cell disorder
• not necessarily absolute absence of thymus
• *TRIAD; conotruncal cardiac anomalies, hypoplastic thymus, hypocalcemia from parathyroid hypoplasia

Question 42

Identify primary immunodeficiency

• 3 months old male with prolonged bleeding with circumcision. Has had pneumonia with strep and was diagnosed with PJP. History of significant eczema
• lab; IgG normal, IgA high, IgM low, mildly decreased T cells, thrombocytopenia with a low MPV (mean platelet volume)

Answer 42

WISKOTT-ALDRICH SYNDROME (WAS)
- x linked diseased characterized by thrombocytopenia with small platelets, eczema, cellular and humoral immunodeficiency, autoimmune disease and malignancy.

Question 43

Identify primary immunodeficiency

• 10 y.o male, wheelchair bound die to progressive ataxia, dysarthria, and choreoathetosis. History of recurrent sinopulmonary infections
• lab; IgG low, IgA low, IgM High, total CD3 low, NK cells and B cells normal number, decreased T cell proliferation to mitogens

Answer 43

ATAXIA TELANGIESTASIA (B and T cell defect)

• autosomal recessive
• chromosomal breakage syndrome xterized by progressive cerebellum neurodegeneration, immunodeficiency, radiosensitivity, increased cancer susceptibility
• ATAXIA, ANGIOMA, IgA DEFICIENCY

Question 44

The follwoing are in what class of deficiency

SCID • Wiskott-Aldrich • Ataxia Telangiectasia • DiGeorge Syndrome • Chronic Mucocutaneous Candidiasis • IL-12/IFN gamma axis • X-linked lymphoproliferative disorder • Ectodermal dysplasia with immune deficiency • WHIM syndrome

Answer 44

CELLULAR AND COMBINED IMMUNE DEFICIENCY

Question 45

Explains the following terms

1. Transplant from one part of the body to another (e.g trunk to arm)
2. Between genetically identical twins or inbred strain
3. Between different members of same species (man to man)
4. Between members of different species (pig to man)

Answer 45

1. Autograft
2. Isograft
3. Allograft
4. Xenograft

Question 46

Graft rejection shows specificity and memory - mediated by lymphocytes.

What genes (2) contribute the most to rejection of graphs?

**why or how do you get immunologic reactions

Answer 46

1. MHC (major histocompatibility complex)
   - determines if you will reject organ or not
2. HLA (human leukocyte complex)
   - Better survival the closer the donor and recipient are on the graft survival graph

• *Allogeneic MHC molecules containing peptides derived from allogeneic cells may look like self MHC molecules plus bound foreign peptides
• represents immunologic cross-reaction

Question 47

Identify the following processes

1. Self MHC molecule presents foreign peptide to T cell selected to recognize self MHC-foreign peptide complexes
2. The self MHC-restricted T cell recognizes the allogeneic MHC molecule whose structure resembles the self MHC-foreign peptide complex
3. The self MHC-restricted T cell recognizes a structure formed by both the allogeneic MHC molecule and the bound peptide

Answer 47

1. Normal Immunologic response
2. Allorecognition
3. Allorecognition

Question 48

Identify the following types of induction of graft responses

1. T cells may recognize the allogeneic MHC molecules on the graft
   - displayed by donor DCs
   - processed and presented by host DCs
   - T cells become activated
2. If graft cells are ingested by recipient DCs
   - donor alloantigens are presented by self MHC molecules on recepient APCs

Answer 48

1. Direct recognition
   - T cell recognize unprocessed allogeneic MHC molecule on graft APCs
2. Indirect recognition
   - T cell recognize processed peptide of allogeneic MHC molecule bound to self MHC molecule on host APC

Question 49

Identify 4 types of transplant rejection and timeline of occurrence

Answer 49

1. Hyperacute; within minutes (pre-existing antibodies respond)
2. Acute; weeks to months- if pt stop taking immunosuppressant drug (cellular and humoral)
3. Chronic; months to years (cellular and humoral)
4. Graft vs Host disease ; timeline varies

Question 50

Identify rejection type

Hyperacute

1. timeline
2. what cells do you see first? (In what 3 organs? - kidney transplant)
3. What Changes? (Necrosis? Thrombosis?)
4. Using flurescence, what do you see in vessel wall?
5. what specific antibody responds?

Answer 50

• organ starts turning black
  1. IMMEDIATE reaction (similar to what you see in blood transfusion rejection)

2. See POLYMORPHONUCLEAR NEUTROPHILS FIRST; in arteries, glomeruli (kidney gets lots of blood flow), peritubular capillaries
3. Changes can be DIFFUSE; Thrombotic occlusion of capillaries, Fibrinoid occlusion of arterial wallls (later on), Kidney cortex INFARCT and necrosis - non functional kidney must be removed
4. **You will see IMMUNOGLOBULIN and COMPLEMENT in vessel wall (fluorescence staining)
5. The alloantigens-specific antibody is IgG

Question 51

Identify type of rejection - days after transplant or months if you stop taking immunosuppressant med

1. Timeline
   - What immune response mechanisms? (2)
   - Can it be reversed?
2. What type will you see infiltration of mononuclear cells (CD8, lymphocytes etc)
   - end result?
3. What type do you see antibodies/ what is this inflammation called?
   - end result?

Answer 51

Acute Rejection
1. DAYS AFTER transplant or MUCH LATER if patients stops immunosuppressant drug
◦ Both humoral and cellular mechanisms
◦ Can be REVERSED (fix cellular mechanisms with immunosuppressant)

2.
A. ACUTE CELLULAR REJECTION; Infiltration of MONONUCLEAR cells, endothelitis (CD8), tubules infiltrated with lymphocytes called TUBULOINTERSTITIAL REJECTION)
◦ End up with necrosis
◦ Histology slide; see lots of blue ducts around kidney tubules

B. ACUTE HUMORAL REJECTION; involve antidonor antibodies called REJECTION/NECROTIZING VASCULITIES (necrosis of endothelial cells, thrombosis, Ig and complement and polymorphonuclear cells in vessel wall), proliferative vascular lessions (less severe, intima thickening, similar to arteriosclerosis - can lead to organ INFARCT and atrophy)

Question 52

Identify type of rejection - months to years

1. What happens to creatinine levels?
   - main problem that occurs that leads to tubular atrophy?

**another problem that occur

Answer 52

Chronic Rejection; Months to years
1. Slow rise in creatinine

2. INTERSTITIAL FIBROSIS - lead to TUBULAR ATROPHY (loss of renal parenchyma) - glomerular responds (chronic transplant glomerulopathy - duplication of basement membrane)
   ◦ Image; Low level reaction mediated by lymphocytes - proliferation of vessel walls (occluded with fibrosis)

**Graft arteriosclerosis

Question 53

1. What rejection type occur primarily in BONE MARROW transplant?
2. What causes this?
3. target organs (S&S)
4. What do you do to prevent rejection?

Answer 53

1. Graft vs Host Disease
   - also occur after liver transplant due to large numbers of lymphocytes (T cells) transplanted, blood transfusion not irradiated (rare)
2. Caused by reaction of grafted T cells with alloantigens of recipient
   - Grafted Immunocompetent T cells reject host cells with “foreign” peptides.
3. target organs; skin, liver, intestine (rash, jaundice, diarrhea, hepatosplenomegaly)
4. To prevent, do ABO and HLA cross-matching

Question 54

Identify the GVH (graft host disease) type

‣ Skin; RASH, desquamation, apoptosis of cells in EPIDERMIS
‣ In liver; jaundice and destruction of small bile ducts
‣ In GI tract; GI bleeding from mucosal ulceration
‣ Immune system; immunosuppressed patient susceptible to infections

• do you get abundant lymphocytes infiltrating?
• what mediates it (2)

Answer 54

Acute GVH

• Don’t get abundant lymphocytic infiltrate
• mediated by CD8 T cell and cytokines

Question 55

Identify the GVH (graft host disease) type

‣ Skin; scleroderma (rheumatic disease), increased fibrosis (tight skin), lose appendages in DERMIS
‣ GI tract; inflammation and esophageal strictures, GI bleeding
- Liver; chronic cholesterol jaundice

Answer 55

Chronic GVH

Question 56

What is the hierarchy of donor acceptance from easiest to hardest based on HLA matching (5 organs)

Answer 56

Liver > Heart > Kidney > Islet&raquo_space; Skin

Question 57

Identify 6 different approaches to making a differential diagnosis

Answer 57

1. Anatomic approach; think through anatomic structures (e.g eye, ear)
2. Systems approach; body systems (Cardio, GI, etc)
3. Possibilities approach; gunshot approach (google stuff)
4. Probabilistic approach; most likely based on presentation
5. Prognostic approach; think first about what could kill a patient (order of severity)
6. Pragmatic approach; diagnoses most responsive to treatment

**Apply multiple approaches so as not to miss anything

Question 58

What is an acronym used to remind you of various categories when making a differential Dx

Answer 58

VINDICATES
Vascular 
Infection 
Neoplasm (cancer) 
Drugs 
Idiopathic 
Congenital 
Autoimmune 
Trauma 
Endocrine (metabolic) 
Somatic (psychiatric)

Question 59

Identify the approach to differential Dx

1. • consider all the diseases the patients may have as equally likely based on clinical presentation
   • NOT EFFICIENT/EFFECTIVE
   • used in early stage of medical training
2. • MOST COMMON method
   • determine what diagnosis is most likely based on patient clinical presentation
   • diagnosis with the highest pre-test probability (before further testing is done)

Answer 59

1. Possibilities approach

2. Probabilistic approach

Question 60

Prioritizing the differential diagnosis

1. Aka working diagnosis
2. Not as likely but are potentially serious and treatable, common and will include MUST NOT MISS diagnosis

Answer 60

1. Leading hypothesis

2. Active alternatives

Question 61

1. How is glucocorticoid released?
2. How does glucocorticoid work? (Action)
   - how long for cortisol to start working?

Answer 61

1. HPA axis (hypothalamic-pituitary-adrenal axis)
   - STRESS stimulates the hypothalamus (CRH neurons)
   - CRH stimulates anterior pituitary (corticotrophes - ACTH)
   - ACTH stimulate adrenal cortex (fasciculata cells - stimulate cortisol release)
   - Cortisol then INHIBIT Immune system (lymphocytes, macrophages/monocytes, neutrophils) thereby INHIBIT INFLAMMATION (IL1, IL2, IL6, TNF alpha)
2. Action (2-3 days to work)
   - glucocorticoids bind to cytoplasmic receptor (glucocorticoid receptor)
   - translocate as a complex into the nucleus
   - modulate genes and proteins depending on target

Question 62

Identify the properties/effects of glucocorticoid on the following

1. Metabolism
2. Calcium
3. Cardiovascular
4. Inflammation
5. Endocrine
6. Bone

• *what is the MIAN NON-ENDOCRINE USE of glucocorticoid?
• *what is the endocrine use?

Answer 62

1. Gluconeogenesis (decrease glucose utilization/metabolism), lipolysis, and proteolysis
2. Decrease calcium absorption (Negative calcium balance)
3. Cardio
   - HTN becuase it stimulate alpha 1 receptors.(hypernatremia, hypokalemia because it can bind to aldosterone at high concentration )
   - Polycythemia
4. ANTI-INFLAMMATORY; Main Non-endocrine use
   - increase lipocortin levels (inhibits phospholipase A2 activity)
   - reduce NF-kappa B levels which lead to reduces levels of proteolytic enzymes, vasoactive cytokines, chemoattractant cytokines, COX-2, NOS
5. Endocrine
   - Thyroid
   - FSH/LH
6. Bone (reabsorption decrease?)
   - decrease bone formation by decrease osteoblasts activity

Question 63

1. Identify

• release is modulated by RAAS (renin-angiotensin system)
• regulate sodium, water and potassium

2. give example and where do they act? (What will stimulate this?)
3. So cortisol levels change due to circadian rhythm, does this drug change? Do you have to give it at specific time?

Answer 63

1. MINERALOCORTICOID
   - Aldosterone act at distal tubules and collecting ducts to; increase sodium and water reabsorption and excrete potassium
2. Aldosterone is stimulated by;
   - Hyperkalemia
   - Indirectly by decreased plasma volume (RAAS) and hyponatremia
3. Aldosterone levees are the same in the plasma when morning of evening so it doesn’t matter what time you give it

Question 64

Identify the diseases associated with glucocorticoid

1. Excess cortisol (2)
2. Insufficiency (2)

Answer 64

1. Excess
   A. Pseudo Cushing’s ; caused by stress, obesity, malnutrition, chronic alcoholism, bacterial infection, anorexia nervosa, chronic exercise
   B. Cushing’s syndrome ; ACTH dependent and independent
2. Insufficiency
   A. Addison’s ; primary (high ACTH, cortisol and aldosterone low) and secondary (everything low)
   B. Congenital Adrenal Hyperplasia (CYP21 deficiency - 21 beta hydroxylase)

Question 65

1. Identify condition
   - A physiological hypercortisolism associated with disorders other than Cushing’s syndrome
2. What causes this? (5 grps)

Answer 65

1. Pseudo Cushing’s
2. • Inflammatory stress (bacterial infection)
   • Severe obesity (visceral obesity or polycystic ovary syndrome)
   • Malnutrition, anorexia nervosa or intense chronic exercise
   • psychological stress, depression, melancholy
   • chronic alcoholism (occasionally)

Question 66

1. The following are signs and symptoms of what disease?

• central obesity, round moon face
• fat pads around neck (buffalo hump)
• excessive sweating
• Muscle wastage
• Skin straie (why?)
• euphoria, psychosis and depression
• *How is this disease first diagnosed?

2. Identify 2 forms/types of the disease

Answer 66

1. CUSHION’S SYNDROME
   - skin straie due to loss of connective skin tissue
   - Cushing’s is often diagnosed due to PSYCHIATRIC ISSUES (depression)
2. A. ACTH dependent (pituitary tumor)
   - excess ACTH secretion lead to adrenocortical hyperplasia
   - most is from pituitary hypersecretion of ACTH (Cushing disease)
   - Ectopic secretion of ACTH or CRH
   - exogenous ACTH

B. ACTH independent (exogenous glucocorticoids)

• IATROGENIC/FACTITIOUS (exogenous long term glucocorticoid use)
• adrenocortical adenomas and carcinomas

Question 67

Identify the various test you can use to test cortisol levels

1. Not truly representative because it only tells you cortisol levels are high (can have false +ve in people who drink lots of water)
2. Not useful in patients with sleep disorders or shift workers. Why?
3. Suppression test used to assess the status of HPA acids and for differential Dx of adrenal hyperfunction
4. Metyrapone test

Answer 67

1. 24 hour urine cortisol
2. Late night salivary cortisol
   - cortisol levels are lowest in morning (except in people that stay up at night - circadian rhythms are screwed)
3. Dexamethasone test; high potency glucocorticoid
   - should lead to decrease in ACTH and then cortisol (negative feedback on HPA axis)
   - use dexamethasone for lab test because it doesnt interfere with lab test for cortisol

Question 68

What are teh treatment options of Cushing’s disease if caused by;

1. High exogenous glucocorticoid ‘
2. Tumors

Answer 68

1. High exogenous use (Cushing syndrome)
   - reduce dose (taper down)
2. Tumor
   A. Surgery
   B. Treatment options
   - block and replace; use for pts with erratic cortisol secretion (totally block teh secretion then give glucocorticoid replacement when levels are extremely low)
   - Normalization; goal to reduce cortisol levels to normal. Used in pts with invariant hypercoticolism

Question 69

Give examples of the following drugs used in Cushing syndrome to reduce cortisol levels

1. Inhibit cortisol production
2. Adrenolytic
3. Inhibit cortisol action

Answer 69

1. Inhibit production
   - A Aminoglutethimide (cytadren) *OFF MARKET
   - K Ketoconazole (NIZORAL)
   - M Metyrapone (metopirone)
   - E Etomidate (anesthetic drugs block CYP11B1); only give IV in hospital setting
2. Adrenolytic
   - MT Mitotane
3. Inhibit action of cortisol
   - Mifepristone(RU-486); medical abortion

Question 70

1. Identify medication

• Antifungal agent
• Inhibits CYP17 (17 alpha hydroxylase) with higher doses (inhibits glucocorticoid and androgen synthesis)
• even higher doses CYP11A1 (cholesterol desmolase) inhibits all steroidogenesis
• inhibits corticotroph adenylate cyclase activation (reduces ACTH secretion at therapeutic doses)

2. Used in what disease?
3. Side effects? (1)
4. Drug interactions?

Answer 70

1. KETOCONAZOLE (inhibit steroidogenesis)
2. Cushing’s disease, anti fungal agent
3. S.E - Adrenal insufficiency (liver toxicity, headache, sedation, nausea, gynecomastia, impotence, decreased libido)
4. Drug interactions
   - strong inhibitor of CYP1A2 (cytochrome P450), CYP2C9 and CYP3A4; so can increase levels of P-glycoprotein substrates (because cytochrome P450 inhibits p-glycoprotein)
   - Do not use with ergot derivatives, cisapride or triazolam (due to risk of potential fatal cardiac arrhythmias)

Question 71

1. Identify medication
   Mechanism; selective inhibitor of CYP11B1 (11 beta hydroxylase) - reduce biosynthesis of cortisol or cortisone (11-DOC to cortisone or 11-deoxycortisol to cortisol)
2. Identify use
3. What route best administered? Half life?
4. Side effects
   - is it better than kecotonazole?

Answer 71

1. METYRAPONE (inhibit cortisol synthesis)
2. • adrenal neoplasms or tumors producing ACTH ectopically
   • Diagnostic test for CUSHING’S SYNDROME
   • Give every 4 hrs for 24 hrs - if cortisol reduces and ACTH increases (Cushing disease)
3. Oral administration
   Half life is 20-26 minutes
4. S.E (worse than kecotonazole)
   - Hirsuitism; due to increased synthesis of adrenal androgens
   - nausea, headache, sedation and rash

Question 72

Identify medication

• acts in adrenocortical cell mitochondria
• **INHIBIT CYP11B1 (11 beta hydroxylase) and cholesterol side-chain cleavage (CYP11A1) enzymes
• Metabolized into an acyl chloride that binds to important macromolecules in the mitochondria, causing mitochondrial destruction and necrosis of adrenocortical cells
• distributes to fatty tissue and has long term effect
• • Can you used alone or in supplement with what med?
• *Any contradictions

Answer 72

MITOTANE

• Need to supplement with EXOGENOUS GLUCOCORTICOIDS
• Not used in pregnancy - CATEGORY X

Question 73

Identify medication

• blocks release of glucocorticoid receptors from chaperone proteins
• also used as progesterone antagonist (ABORTION MORNING AFTER PILL)

**What side effect must you watch for?

*what conditions used for?

Answer 73

MIFEPRISTONE (RU-486); glucocorticoid receptor antagonist

S.E
VAGINAL BLEEDING, abd pain, GI upset, diarrhea and headache

Used in;

• inoperable ectopic ACTH tumors
• Adrenal carcinomas unresponsive to other treatment
• MEDICAL ABORTION
• Cushing;s syndrome (rare)

Question 74

Identify conditions

1. Structural/functional lesion of the adrenal cortex
   - HIGH ACTH levels (lack negative feedback)
   - LOW glucocorticoid and mineralocorticoid
2. Pituitary or hypothalamic deficiency
   - LOW ACTH levels
   - LOW glucocorticoids and adrenal androgens

**what synthetic ACTH can you use to treat?

Answer 74

1. Primary Adrenocrotical insufficiency (Addison’s disease)
2. Secondary (problem in pituitary or hypothalamus)

**COSYNTROPIN - synthetic ACTH
A. Primary (Addison’s); administer cosyntropin, measure plasma cortisol prior and 30-60 min after ACTH levels high, but low cortisol levels
- S&S; weakness, weight loss, anorexia, hypotension, DARK SKIN PIGMENTATION (due to POMC that ACTH stimulates), hyponatremia
B. Secondary insufficiency
- baseline levels of ACTH low and cortisol levels low
- malaise, anorexia but NO HYPERPIGMENTATION

Question 75

Identify the conditions you use these treatments for?

1. • Treat with glucocorticoids and mineralocorticoid (hydrocortisone and cortisone preferred, supplement with fludrocortisone to give a higher mineralocorticoid effect)
   • Acute insufficiency is life threatening, should also consider isotonic NaCl and glucose therapy in conjunction with steroids
2. • treat with hydrocortisone or prednisone (mineralocorticoid may not be needed)

Answer 75

1. Primary insufficiency (Addison’s disease)
   - hyponatremia, hyperkalemia, hypoglycemia, hypotension (opposite of Cushing syndrome)
2. Secondary Insufficiency

Question 76

Identify the condition

• non classic post puberty presentation (mild androgen excess hirsuitism, amenorrhea)
• mutation or deficiency of CYP21 (21 beta hydroxylase which converts DHEA to 11-DOC) so you have increased levels of DHEA (17-hydroxyprogesterone) and androgens
• *What are the classic severe deficits in males vs females?
• *Treatment

Answer 76

CAH (Congenital Adrenal Hyperplasia)

Females; psedudohermaphroditism
Males; normal at birth from precocious puberty

Treatment
- corticosteroid replacement therapy (hydrocortisone) females with classic stuff - treat in utero

Question 77

What’s the difference between time of administration of corticosteroids vs mineralocorticoids

Answer 77

1. Corticosteroids
   - stimulate normal circadian rhythm
   - give more in the morning and less in the evening ‘
2. Mineralocorticoid
   - given once a day (doesn’t matter what time because levels don’t change through the day)

Question 78

Identify disease process and treatment option

1. Hypertension and hypokalemia
2. How do you treat (2)? S.E of drugs
   - which has more side effects?
   - which is less expensive?

Answer 78

1. Aldosteronism
2. Tx with surgery first and then aldosterone antagonist
   A. Spironolactone (MINERALOCORTICOID RECEPTOR ANTAGONIST but also a progesterone agonist and androgen antagonist)
   - breast tenderness and menstrual irregularities in women
   - impotence, decreased libido and gynecomastia in men

B. Eplerenone
- less side effects and more expensive

Question 79

1. Which drugs have the highest anti-inflammatory potency?

2. Which drug has the highest craziest mineralocorticoid potency?

Answer 79

1. Betamethasone and Dexamethasone (glucocorticoid)
   - no relative mineralocorticoid potency (0)
   - long half life (>36 hrs)
2. FLUDROCORTISONE (mineralocorticoid)
   - be careful, only used when you need aldosterone replacement
   - intermediate half life (12-36hrs)

**Potency for glucocorticoid
Betamethasone/dexamethasone > FLUDROCORTISONE > triamcinolone = methyprednisolone > prednisone > hydrocortisone > cortisone

**Potency for mineralocorticoid
FLUDROCORTISONE > prednisone/ cortisol/cortisone > triamsinolone = betamethasone

Question 80

Cortisol - cortisone shuttle

1. What enzyme activates cortisol?
2. What deactivates cortisol?

**Explain metabolism of cortisol

**How are most cortisol administered?

Answer 80

1. 11B -HSD1 (11 beta hydroxysteroid dehydrogenase type 1) isoenzyme activates cortisol (cortisone - cortisol)
   * *Found in most glucocorticoid target tissues
2. 11B- HSD2 (11 beta hydroxysteorid dehydrogenase type 2) isoenzyme deactivates cortisol (cortisol - cortisone)
   * *Found in mineralocorticoid target tissues
   * *Kidney, colon, salivary glands and also placenta

• *Metabolism
• Hepatic conjugation with glucoronides/sulfate; first pass effect varies by steroid
• Renal excretion
• *ALL corticosteroid can be administer ORAL
• some can be aerosol, topical, IV, IM

Question 81

Corticosteroid only treat effects of disease not the actual disease itself

**What disease is the except to this? (Glucocorticoid like cortisol and mineralocorticoid like fludrocortisone actually treat this disorder)

Answer 81

PRIMARY ADRENOCORTICOID DEFICIENCY (Addison’s disease)

Question 82

1. What withdrawal effects (on HPA) would you experience from sudden stop in cortisol therapy
2. How can you prevent this?
3. Adverse effects are associated with what 2 things?
4. What prevent probability of adverse effects

Answer 82

1. HPA suppression
   - suppress HPA axis due to feedback loop that inhibits ACTH release
   - results in decreased ACTH induced cortisol secretion
   * leads to secondary adrenocortical insufficiency (severity depends on individual/dose/duration of therapy and can last up to 12 months)
2. To prevent; TAPER steroid following prolonged therapy
3. Adverse effects associated with;
   - dose
   - prolongation of therapy (lead to Cushing’s syndrome)
4. Short term/ LOCALIZED administration reduces the probability of adverse effects

Question 83

Adverse effects of cortisol use

• identify the specific efffects of prolonged cortisol use of the follwoing;

1. Cardio
2. CNS
3. GI
4. Metabolic
5. Eye
6. Osteoporosis
7. Immune system

Answer 83

CUSHING SYNDROME
1. Cardio; HTN, edema, sodium and water retention, depends on mineralocorticoid activity of the corticosteroid, hypokalemia

2. CNS; euphoria, depression, psychosis, insomnia
3. GI; peptic ulcer
4. Metabolic; hyperglycemia, muscle catabolism, hyperlipidemia, fat deposition (moon face), straie
5. Eye; cataracts, glaucoma
6. Osteoporosis; negative Ca+ balance (cause increased parathyroid hormone), inhibits osteoblasts
7. Immune system; increased susceptibility to infection, esp viral and fungal

Question 84

Identify the therapeutic uses of glucocorticoids (8)

Examples of glucocorticoids; cortisol, prednisone, methyprednisolone, triamcinolone, betamethasone, dexamethasone

Answer 84

1. EXCELLENT ANTI-INFLAMMATORY ACTIVITY
2. Palliative not curative - underlying cause still present (only treat the symptoms)
3. Used for steroid responsive conditions
4. **Use only when less toxic substances are ineffective e.g for arthritis, use NSAIDs first
5. **Use the minimum effective dose (in general one large dose has minimal side effects)
6. Administer LOCALLY if possible (topical administration will lessen systemic effects)
7. **AVOID RAPID WITHDRAWAL
8. **Glucocorticoid may suppress signs and symptoms of diseases or interfere with diagnostic tests

Question 85

1. Why do they tell you to use glucocorticoid in the morning?
2. Why use it every other day once in remission?

Answer 85

1. Administer in the morning to duplicate circadian rhythm (cortisol levels are usually highest in the mornings)
2. Every other day therapy
   - REDUCES SUPPRESSION OF HPA AXIS
   - better compliance
   - less side effects

Question 86

What types of non-endocrine diseases can you use glucocorticoid for? (10)

**and how should you use the medication?

**what is MAJOR side effect of using it for respiratory disease?

**Can you use for anaphylaxis? What is first drug to use in anaphylaxis?

Answer 86

1. Rheumatic Disorders
   - start with high dose and taper down
   - use w/ other immunosuppressant
   - **caution if virus is contributing factor to disorder
   - **In RHEUMATOID ARTHRISTIS; it is not the first line of drug. Only use when non-responsive to NSAIDs. Use intra-articular injections for major symptoms - non inflammatory degenerative disease like osteoarthritis (every 3 months)
2. Respiratory disorders (Asthma and COPD)
   - low systemic side effects in inhalation
   - most common side effect is ORAL CANDIDIASIS (use space or rinse your mouth out afterwards)
3. Allergies
   - NOT USED FOR SEVERE ALLERGIC REACTIONS LIKE ANAPHYLAXIS. Use epinephrine for anaphylaxis
   - used to control short duration allergic disorders (poison ivy) in conjunction with antihistamines
4. Maturation of lungs (premature infants)
   - cortisol is a regulator of lung maturation (babies 24-34 weeks)
5. Collagen disorders
6. Dermatologic problems (eczema)
7. GI (Crohn’s Disease and ulcerative colitis)
   - used when other therapies fail
   - pay attention becuase glucocorticoid can mask symptoms of complications such as intestinal perforation and peritonitis
8. Organ transplant (prednisone)
   - low doses useful in acute rejection
   - higher dose required in established rejection
   - GIVE IN CONJUNCTION WITH OTHER AGENTS
9. Spinal cord injury
10. Cancers
    – Acute Lymphocytic leukemia
    – Control hypercalcemia

Question 87

Identify contraindications/precautions for corticosteroid on the following;

1. Pregnancy, breast feeding and children
2. Immunosuppression
3. Metabolic
4. Aging
5. Psychiatric

Answer 87

1. Pregnancy and breast feeding
   - CATEGORY C (dexamethasone); can cause cleft palate and still birth
   - DO NOT BREAST FEED if taking systemic steroid; it can distribute to baby via breast milk
   - potential for growth and development inhibition in children
2. Immunosuppression
   - cortisol can mast viral and fungal infections (because it reduces inflammation). Avoid if possible
   - if on prolonged corticosteroids pls avoid exposure to viral infections. AVOID CONCURRENT LIVE VIRUS VACCINATIONS
3. Metabolic
   - be careful with CHF and HTN patients (steroid induce hypertension and weight gain)
   - be careful with DIABETIC pts (steroid cause hyperglycemia)
4. Aging
   - be care in ELDERLY/ POST-MENOPAUSE induce osteoporosis, long bone fraction, femoral/humoral Head necrosis
   - Give high protein didn’t and CALCIUM AND VITAMIN D SUPPLEMENT
5. Psychiatric
   - be careful in pts with psychosis, emotional disturbances and seizure disorders **can exacerbate these symptoms

Question 88

What are drug interactions of cortisol and how can this be dangerous

1. What enzyme does cortisol induce? How does this affect estrogen
2. What promote cortisol metabolism?
3. What induce elevation of corticosteroid binding proteins? What is implication of this?

Answer 88

1. Corticosteroid can induce CYP3A4 (cytochrome P450) which can reduce levels of other drugs
   - estrogen is metabolized by 3A4; some contraceptives might be less effective cause it is metabolized quickly
   - several antiviral (ritinovir, lopinavir)
2. Corticosteroid metabolism is promoted by HEPATIC MICROSOMAL ENZYME INDUCERS (barbiturates, carbamazepine, phenytoin)
3. Estrogens induce elevation of corticosteroid binding proteins. Increasing circulating Half life and reduce free concentration

Question 89

Identify medication

MoA; promotes glucocorticoid synthesis and release by adrenal gland (ACTH ANALOG)
- has a short half life of 15 minutes

Answer 89

COSYNTROPIN (ACTH analog)

Question 90

Immunosuppression

1. What immune responses are easier to suppress (primary or secondary?) why?
2. What do immunosuppressive agents target?
3. When does immunosuppression therapy work best?

Answer 90

1. Primary immune response easier to suppress for 2 reasons;
   - Primary takes longer to initiate (so you can fix?)
   - No drug can stop/interrupt a secondary immune response
2. Target different aspects of T cell activation
3. Work best if used before rather than after exposure to the immunogenicity

Question 91

1. Identify 3 clinical uses of immunosuppressants
2. Identify 2 limitations to therapy
3. Transplant-related immunosuppression
   - transplant rejection mediated by cells mainly?
   - what cells also play role?
   - 3 types of rejection

Answer 91

1. A. Organ transplantation (you need to suppress immune system first before transplant)
   B. Selective immunosuppression (decrease Rh hemolytic disease in newborns)
   C. Autoimmune disorders
2. A. Increased risk of INFECTION (usual plus oppurtunistic organisms)
   B. Increased risk of CANCER; lymphomas, skin cancer and virus-associated cancers
3. A. T cells play main role
   B. B cells also play role via antibody production
   C. Hyperacute, acute and chronic rejection

Question 92

1. Identify immunosuppressive agents based on target site of action

Site of action (MoA);

• drug response elements in DNA (2 types)
• VERY POTENT immunosuppressive agents
• Not specific for T cells as they affect multiple immune cells and non-immune cells
• induce non-specific immunosuppression
• ANTI-INFLAMMATORY (suppress the expression of cytokines)

2. Use (2)
3. Adverse effect

Answer 92

1. GLUCOCORTICOID (prednisone and methyprednisolone)
2. Use (alone or in combination of other drug)
   - organ transplant rejection (use at start of transplant or to prevent acute rejection)
   - autoimmune disease
3. Adverse effects
   - HTN, hyperglycemia, psychosis, mood symptoms

Question 93

1. Identify immunosuppressive agents based on target site of action

Site of action; CALCINEURIN INHIBITOR (inhibit phosphatase activity).
- Relatively specific for T cells. Why or how?

2. MoA
   - what complexes do they form for action?
3. Effects (what does inhibition of calcineurin cause?)
4. Uses
5. Adverse effects**

Answer 93

1. CYCLOSPORINE AND TACROLIMUS
2. MoA;
   - cyclosporine/cyclophilin complex or Tacrolimus/FKBP-12 complexes to inhibit calcineurin
3. • DRUG IS SPECIFIC FOR T CELLS (complex inhibit calcineurin which is specific for T cells). Tacrolimus is 100x more potent that cyclosporine.
   • Inhibit calceneurin - inhibit NFAT - decrease IL2 (decrease T cell activation and proliferation) - increase TGF beta (immunosuppressant but also promote fibrosis)
4. Use
   - prevent rejection of kidney, liver and cardiac transplants (+-corticosteroid)
   - Autoimmune disorders (rheumatoid arthritis, Crohn’s disease, nephrotic syndrome)
5. Adverse effects
   - Nephrotoxicity
   - HTN***
   - Neurotoxicity (Tacrolimus)
   - Hepatotoxicity

Question 94

1. Identify immunosuppressive agents based on target site of action
   - MTOR INHIBITOR (MTOR protein kinase is involved in cell cycle progression
2. MoA
   - this drugs bind to something that another drug binds to ?
   - which of the 2 drugs has a shorter half life
3. Effects
   - what cell cycle phase is blocked?
4. Uses
5. Adverse effects***

Answer 94

1. SIROLIMUS AND EVEROLIMUS
2. MoA
   - Sirolimus and Everolimus bind to FKBP-12 (Tacrolimus also does)
   - The complex does not affect calcineurin activity tho; its inhibits mTOR kinase activity
   - EVEROLIMUS has a SHORTER HALF LIFE than sirolimus
3. Effects
   - bocks G1-S transition phase of cell cycle
   - blocks proliferation of activated T cells
4. Use; similar to calcineurin inhibitors (cyclosporine/tacrolimus)
   - prevent rejection of kidney, liver and cardiac transplant
   - autoimmune disorders
   - Sirolimus-eluding stents are used to inhibit restenosis of blood vessels
5. Adverse effects
   - **HYPERLIPIDEMIA (increase in serum cholesterol and triglycerides)
   - delay graft function and delayed wound healing
   - anemia, leukopenia, thrombocytopenia

Question 95

1. Identify 2 cytotoxic drugs (nonselective agents)
   - drugs MoA
   - what potentiates one of the drugs ?
   - what decrease absorption of the other drug?

Answer 95

1. Azathioprine (AZA)
   - inhibit DNA synthesis (block T cell expansion)
   - If taking allupurinol, please reduce AZA dose (else lead to toxicity)
2. Mycophenolate mofetil (MFF)
   - not as toxic
   - selectively inhibit T and B cell proliferation by shutting the IMPDH pathway
   - antacids decrease absorption of drug

Question 96

1. Identify immunosuppressive agents based on target site of action
   - prodrug that is converted to 6-mercaptopurine (6-MP) in vivo
2. MoA; Ultimately, 6-MP, and 6- MP metabolites can be incorporated into DNA (inhibits DNA synthesis), 6-MP also inhibits the de novo pathway of purine synthesis.
   * *why do lymphocytes depend on de novo synthesis of purine?
3. Uses
4. Drug interaction
5. Adverse effects

Answer 96

1. AZATHIOPRINE (AZA) - cytotoxic non-selective agent
   - 6-MP inhibits DNA synthesis and the de novo pathway of purine synthesis
2. Lymphocytes lack the purine salvage pathway so they depend on de novo synthesis of purines
3. Uses
   - adjunct for prevention of organ transplant rejection
   - rheumatoid arthritis
4. Drug interaction
   - if ALLUPURINOL is given, reduce AZA dose. Xanthine oxidase catabolizes AZA metabolites (Toxic)
5. Adverse effects
   - not selective for T cells
   - suppress proliferation of many hematopoietic cell types so cause; bone marrow suppression, leukopenia, thrombocytopenia and anemia

Question 97

1. Identify immunosuppressive agents based on target site of action
   - Prodrug converted to mycophenolic acid (MPA) in the gut. MPA is a reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH). Inhibition of IMPDH inhibits de novo synthesis of guanine.
2. MoA
3. Uses
   - used in combination of what 2 drugs?
4. Adverse effects
   - is it more toxic that the other cytotoxic drug?
   - what decrease absorption of drug?

Answer 97

1. MYCOPHENOLATE MOFETIL (MFF)
2. MoA
   - selectively inhibits B and T cell proliferation by inhibiting the IMPDH pathway
   - B and T cells lack a purine salvage pathways so they depend highly on IMPDH pathway (inosine monophosphate dehydrogenase)
3. Uses
   - typically used in combination with GLUCOCORTICOIDS and CALCINEURIN INHIBITOR to suppress transplant rejection
4. Adverse effects
   - less toxic that AZA but can cause GI effects and leukopenia
   - ANTACIDS (magnessium and aluminum) decrease absorption

Question 98

Identify 8 antibodies (therapy) used in immunosuppression

Answer 98

1. Muromonab-CD3 (ORTHOCLONE); from mouse
   - T cell receptor complex (blocks antigen recognition)
2. Antithymocyte globulin (ATGAM); from horse
3. IL2 receptor blocking antibodies
   - DACLIZUMAB (from human) and BASILIXIMAB (part chimeric and part human)
4. Anti-CD52 antibody
   - ALEMTUZUMAB (campath-1H)
5. Anti-LFA-1 antibody
   - EFALIZUMAB (inhibit T cell adhesion - OUT OF MARKET)
6. Anti-IL-6 receptor antibody
   - TOCILIZUMAB
7. Anti-CD20 antibody
   - RITUXIMAB
8. Anti-TNF alpha drugs; INFLIXIMAB, CERTOLIZUMAB PEGOL, ADALIMUMAB, ETANERCEPT, GOLIMUMAB

Question 99

1. Identify immunosuppressant antibody
   - Mouse monoclonal antibody against CD3 glycoprotein. CD3 is adjacent to the T cell receptor (TCR) complex
   - MoA; Induces internalization of the TCR, which in turn blocks antigen-mediated activation of T cells.
2. Uses
3. Side effects **

Answer 99

1. MUROMONAB-CD3 (ORTHOCLONE)
2. USE
   - prevent organ transplant rejection
3. Adverse effects
   - **CYTOKINE STORM; cytokine release syndrome - ORTHOCLONE initially activates T cells causing massive release of cytokines
   - anaphylactic reactions
   - CNS toxicity increased risk for infections and malignancy

Question 100

1. Identify immunosuppressant antibody
   - polyclonal antibody from serum of horses or rabbits immunized with human thymus lymphocytes
2. MoA; binds to circulating T lymphocytes to do what 2 things?
3. Uses
4. Adverse effects

Answer 100

1. Antithymocyte globulin (ATGAM)
2. MoA; binds to circulating T lymphocytes which induces lymphopenia (complement-mediated) and decreases T-cell function.
3. Uses;
   - prevent organ transplant rejection
4. Adverse effects
   - serum sickness, nephritis, chills, fever and rashes

Question 101

1. Identify immunosuppressant antibody
   - humanized monoclonal antibodies that target IL-2 receptor (one is humanized - Zu, the other is half chimeric, half human - XI)
2. MoA?
3. Uses

Answer 101

1. IL-2 receptor blocking antibodies
   - DACLIZUMAB and BASILIXIMAB
2. MoA; Inhibit the binding of IL-2 the IL-2 receptor. Blocking IL-2 receptor (CD25) suppress the proliferation of activated T cells.
3. Uses
   A. Daclizumab - for relapsing multiple sclerosis
   B. Basiliximab; prevent organ transplant rejection

Question 102

1. Identify immunosuppressant antibody
   - humanized anti-CD52 antibody

MoA; Binds CD52 on B and T lymphocytes, monocytes, macrophages, and natural killer cells. By this way, it induces apoptosis and T and B cell depletion.

2. Uses
3. Adverse effects

Answer 102

1. ALEMTUZUMAB (campath-1H); humanized anti-CD52 antibody
2. Uses
   - relapsing remitting multiple sclerosis and chronic lymphoid leukemia
3. Adverse effects
   - Depletion of normal neutrophils and T cells
   - Serious myelosuppression

Question 103

1. Identify immunosuppressant antibody
   - humanized anti-IL-6 receptor antibody
2. MoA
3. Uses

Answer 103

1. TOCILIZUMAB (anti-IL-6 receptor antibody)
2. Mechanism
   - It targets both soluble and membrane-bound IL-6 receptors, thus inhibiting the binding of IL-6 to both receptors. Inhibition of IL-6 signaling suppresses the inflammation associated with rheumatoid arthritis.
3. Uses
   - juvenile rheumatoid arthritis
   - Rheumatoid arthritis.

Question 104

1. Identify immunosuppressant antibody

• Chimeric anti-CD20 antibody.
• MoA; Induces B lymphocyte apoptosis by binding to CD20 on malignant B-lymphocytes.

Answer 104

RITUXIMAB (anti-CD20 antibody)

Use

• to chronic lymphoid leukemia
• non-hodgkin’s lymphoma
• rheumatoid arthritis

Question 105

1. The following drugs are under what classification?

• infliximab
• Certolizumab pegol
• adalimumab
• etanercept
• golimumab

2. Use
3. Adverse effects

Answer 105

1. ANTI-TNF alpha drugs
   • Infliximab: chimeric anti-TNFα antibody.
   • Certolizumab pegol: Humanized PEGylated anti TNFα antibody.
   • Adalimumab: Human anti-TNFα antibody.
   • Etanercept: Is a decoy TNFα receptor. Fusion protein made of 2 extra-cellular domains of the TNFα receptor linked by the constant Fc portion of human immunoglobulin 1 (IgG1).
   • Golimumab: Human anti-TNFα antibody.
2. Use
   - rheumatoid arthritis, psoriasis, ulcerative colitis, Crohn’s disease
3. Adverse effects
   - increased risk for infection
   - lymphomas and other cancers

Question 106

Identify 2 fusion proteins

A.

• what are costimulatory modulators? ***
• what complex (fusion proteins) forms?

B. Which is more potent

C. Inhibition of the co-stimulatory induces what?

D. Uses

Answer 106

1. Alefacept; suppress T cell function. Was used in psoriasis but now discontinued
2. ABATACEPT and BELATACEPT ; CTLA-4-IgG1 fusion proteins
   - Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4).
   - Abatacept and Belatacept are CTLA-4-IgG1 fusion proteins.

A. MoA
Abatacept and Belatacept are co-stimulatory modulators. They bind to CD80 and CD86 receptors on APCs. This blocks the
interaction between CD80/CD86 receptors to CD28 (on T cells). In this way, the drugs INHIBIT T CELL ACTIVATION.

B. Belatacept is more potent than Abatacept.

C. Inhibition of the co-stimulatory has been shown to induce tolerance (experimental models)

D. Uses: Juvenile arthritis and Rheumatoid
arthritis. Prevent organ transplant rejection.

Question 107

Identify the drug/agent class

• Treat conditions of immunodeficiency (e.g. AIDS) or to bolster immunity against specific targets, and to suppress some cancers.
• Can act through cellular or humoral immunity or both.
• Magnitude of stimulation can be highly variable.

Answer 107

IMMUNOSTIMULANTS

**used in immunodeficiency like AIDS

Question 108

Identify immunostimulants

• (comes from pooled human plasma)
• Immune globulin contains all immunoglobulin subclasses (IgG > IgM) to provide passive immunity.
• Used in various immunodeficiency states, to prevent measles, hepatitis A, and tetanus for example. Many types of immune globulins available.

Answer 108

NATURAL ADJUVANTS
- Immune Globulins

**pre-formed antibodies given to immunodefiecient patient to prevent - measles, Hep A

Question 109

Identify immunostimulants

• A viable attenuated strain of Mycobacterium bovis; muramyl dipeptide is the active component.
• Stimulates natural killer cells and T cell activity.
• Used primarily in the treatment of bladder cancer.
• Adverse effects — severe hypersensitivity reactions and shock can develop.

Answer 109

NATURAL ADJUVANTS
- Bacillus Calmette - Guerin (BCG) Vaccine

**stimulates the immune system - can be used to treat bladder cancer

Question 110

Identify immunostimulants

- Best known for the severe life threating birth defects it caused when given to
pregnant women (category X).  
- Indicated for the treatment of erythema nodusum leprosum
(ENL) and multiple myeloma. Its mechanism of action is unclear.

Answer 110

SYNTHETIC AGENT
- Thalidomide

**cause sever life threatening BIRTH DEFECTS - CATEGORY X

Question 111

Identify immunostimulants

• Identified because of their antiviral activities, they also have important immunomodulatory activity.  They increase phagocytosis by macrophages, and augment the specific cytotoxicity by T lymphocytes. 
• Indicated for several cancers: hairy cell leukemia, malignant melanoma, follicular lymphoma, AIDS-related Kaposi sarcoma) and
infectious diseases (chronic hepatitis B)

**Adverse effects

Answer 111

INTERFERONS (alpha, beta and gamma)

Adverse effects

• flu like symptoms
• black box warning (pulmonary hypertension)

**used in several cancers and infectious disease

Question 112

Identify immunostimulants

• Mechanism of action – Activates cellular immunity.
• Uses: Indicated for metastatic melanoma, renal cell carcinoma and in AIDS patients.
• Adverse effects: Can induce severe hypotension and life threatening cardiovascular toxicity. Pulmonary edema (capillary leak syndrome) is dose limiting.

Answer 112

INTERLEUKIN-1 (IL2)

**activates cellular immunity

Question 113

Identify immunostimulants

• Glycoproteins produced by monocytes, fibroblasts and endothelial cells. Stimulate increases in the numbers of granulocytes and monocytes. Used to reduce neutropenia in several instances (see clinical implications in table below.)

Answer 113

GCSF aka Myeloid Grwoth factors
- Granulocyte colony stimulating factors

**used to restore low levels of neutrophils (from cancer therapy)

Question 114

Identify

• an exaggerated response resulting in harm to the host

Answer 114

HYPERSENSITIVITY

• the term arose from the clinical definition of immunity as sensitivity, based on the observation that an individual who has been exposed to an antigen exhibits a detectable reaction or is “sensitive” to subsequent encounters with that antigen

Question 115

1. Identify another name for type I hypersensitivity and give examples of conditions (6)
2. What are the pathologic immune mechanisms involved (aka immune cells) - (2)
3. What is the mechanism of tissue injury and disease
   (What causes problems) - (3)

Answer 115

1. Immediate: Type I
   - ALLERGIES; allergic rhinitis, allergic asthma, eczema or atopic dermatitis, some food allergy, some drug allergy, insect venom allergy
2. Immune cells
   - IgE antibody
   - Th2 cells (humoral adaptive immunity)
3. MoA (what cause injury)
   - Mast cells
   - Eosinophils
   - mediators (vasoactive amines, lipid mediators, cytokines)

Question 116

1. Identify another name for type II hypersensitivity and give examples of conditions (6)
2. What are the pathologic immune mechanisms involved (aka immune cells) - (2)
   - where are the antigens located in type II
3. What is the mechanism of tissue injury and disease (3)
   (What causes problems)

Answer 116

1. Antibody-mediated: Type II
   - transfusion reaction, hemolytic disease of the newborn, autoimmune hemolytic anemia, goodpasture syndrome, pemphigus vulgaris, rheumatic fever
2. Immune cells
   - IgM, IgG antibodies against cell surface or ECM antigens
3. Mechanism
   - Opsonization and phagocytosis of cells
   - Complement- and Fc receptor–mediated recruitment and activation of leukocytes (neutrophils, macrophages)
   - Abnormalities in cellular functions, e.g., hormone receptor signaling, neurotransmitter receptor blockade

Question 117

1. Identify another name for type III hypersensitivity and give examples of conditions (3)
2. What are the pathologic immune mechanisms involved (aka immune cells) - (2)
   - where are the antigens located in type III
3. What is the mechanism of tissue injury and disease
   (What causes problems)

Answer 117

1. Immune complex-mediated: type III
   - serum sickness (from vaccines and drug reactions)
   - drug reactions
   - autoimmune disease (rheumatoid arthritis, SLE)
2. Immune cells and antigen location
   - IgM and IgG antibodies form immune complexes with soluble circulating antigens
3. Mechanism
   - Complement- and Fc receptor–mediated recruitment and activation of leukocytes

Question 118

1. Identify another name for type IV hypersensitivity and give examples of conditions (4)
2. What are the pathologic immune mechanisms involved (aka immune cells) - (2)
3. What is the mechanism of tissue injury and disease (2)
   (What causes problems)

Answer 118

1. T cell-mediated; Type IV 
• Contact dermatitis 
• Autoimmune disease (MS, type 1 DM, rheumatoid arthritis) 
• Graft rejection 
• Tumor immunity

2. Immune cells
   - CD4+ T cells (Th1 and Th17 cells)
   - CD8+ CTLs
3. Mechanism
   - Cytokine-mediated inflammation
   - Direct target cell killing, cytokine-mediated inflammation

Question 119

1. What type of hypersensitivity is an immediate reaction that results in release of mediators from IgE-sensitized mast cells
2. Identify 5 components that play role here

Answer 119

1. Type I hypersensitivity (2 phases - immediate and late)
2. • Allergen specific IgE
   • Mast cells
   • Allergen
   • Eosinophils
   • CD4+ Th2 cells

Question 120

1. Identify the differences between immediate and late phases of type I hypersensitivity

• how are mast cells stimulated? (What must occur?**)
• what mediators are stimulated by mast cells
• timeline for both phases

Answer 120

1. A. Immediate (minutes);
   - first exposure to allergen - antigen activation of Th2 cells - release IL4 which induce class switching to IgE in B cells - IgE bind to Fc epsilon receptors which stimulate mast cells - release mediators (vasoactive amines - HISTAMINE, lipid mediators) - contraction of vascular/smooth muscle
   - repeat exposure to allergen - antigen crosslinks preformed IgE on presensitized mast cells - IMMEDIATE DEGRANULATION

B. Late (6-24 hours after repeat exposure to allergen)
- crosslinking of IgE to Fc epsilon receptor stimulate mast cells - release chemokines (which attract inflammatory cells like EOSINOPHILS) and cytokines (leukotrienes) - INFLAMMATION and tissue damage

**Mast cells and basophils are activated by CROSS LINKING ANTIGEN VIA Fc receptors - this helps secrete preformed mediators and cytokines and synthesize lipid mediators

Question 121

Identify biological effects of mast cell mediators (6)

Answer 121

1. Vasodilation (histamines)
2. Vascular leakage (histamines)
3. Bronchoconstriction (lipid mediators - PAF, PGD2)
4. Intestinal hypermotility (lipid mediators)
5. Inflammation (lipid mediators, cytokines - TNF - IL5)
6. Tissue damage (enzymes - tryptase)
   * *Uterine contraction also occur in females

Question 122

1. Identify condition
   - swelling, hypotension, increased HR, difficulty swallowing, wheezing, fluid outflow (diarrhea, vomiting, abdominal cramping in females)
2. Identify treatment of choice

Answer 122

1. SYSTEMIC ANAPHYLAXIS
   - increased capillary permeability and entry of fluid into tissues including tongue
   - reduced oxygen to tisssues
   - irregular heart beat
   - anaphylactic shock
   - loss of consciousness
   - contraction of smooth muscle, throat and airways
   - difficulty swallowing and breathing (wheezing)
2. EPINEPHRINE
   - not antihistamine
   * *Avoid allergen if possible

Question 123

• Progression of allergic symptoms with
age 
• Many chronic asthmatics have hx of
atopic dermatitis 
• Sensitivity to food in infants can be
associated with appearance of allergy to
inhalants later in life

Answer 123

The Allergic March

• You are genetically inclined to allergen exposures
• Allergic early in life leads to more allergies later in life.

**Seasonal allergic rhinitis tend to develop later in life (opposite for other allergies which should normally decrease with age)

Question 124

How do you test for immediate type I hypersensitivity (3)
1 - in vivo (life human)
2- in vitro (lab)

Answer 124

1. In vivo
   A. skin testing; introduce antigen to skin, observe for wheal and flare, occurs within 20 minutes
2. In vitro; ELISA blood test
   A. Allergen specific IgE levels; coat plate with allergen and then add patient serum
   B. Total IgE levels (IgE will be elevated if there is allergy); coat plate with anti-IgE antibody and add patient serum n

Question 125

Identify treatment option for type I hypersensitivity

• Increasing doses of allergen are administered
• Typically injected subcutaneously; also by sublingual and intralymphatic routes although these are less widespread
• In general, this results in a rise in serum IgG blocking antibody levels
• Currently only available for environmental aeroallergens

Answer 125

IMMUNOTHERAPY

• Current research into area of oral immunotherapy for foods is extensive although still not FDA-approved.

Question 126

In type II hypersensitivity, explain how antibodies bind to cell-surface antigen leading to the the following processes

1. Cellular destruction
2. Inflammation
3. Cellular dysfunction

**give examples of disease associations for each

Answer 126

1. Cellular destruction; cell is opsonized (coated) by antibodies, leading to either of;
   - phagocytosis and/or activation of complement system
   - NK cell killing (ADCC- antibody dependent cellular cytotoxicity)
   E.g autoimmune hemolytic anemia, immune thrombocytopenia, transfusion reactions, hemolytic disease of newborn
2. Inflammation; binding of antibodies to cell surface - activation of complement system and Fc receptor-mediated inflammation
   E.g Goodpasture syndrome, rheumatic fever, Hyperacute transplant rejection
3. Cellular dysfunction; antibodies bind to cell surface receptor - abnormal blockade or activation of downstream process
   E.g Myasthernia gravis, Graves’ disease, pemphigus vulgaris

Question 127

Type II hypersensitivity

1. What antibodies involved
2. Involves a circulating antibody and its target antigen. The antigen can be located where?
3. Where do reactions occur?
4. Reactions result in ?
5. Do they always involve complement activation?
6. In ADCC, what antibody is a bridge that links target cells to effector cells?
7. Give examples of effector cells (4)

Answer 127

1. IgG or IgM
2. Antigen location
   - on surface of cell in circulation or
   - in a tissue
3. Reactions occur;
   - in soluble phase in circulation
   - in localized tissue site
4. Often result in CYTOTOXICITY
5. May or may not involve complement activation
6. IgG
7. Effector Ceres; macrophages, eosinophils, NK cells and neutrophils

Question 128

Identify the major tests used in type II hypersensitivity

1. Detects antibodies attached DIRECTLY to the RBC surface
2. Detects presence of unbound antibodies in the serum

• *what conditions do they help diagnose?
• which is used before you transfuse blood

Answer 128

1. Direct Coombs test; measure antibodies directly on surface of RBC
   - helps Dx ; hemolytic disease of newborn, autoimmune hemolytic anemia, transfusion reaction
2. Indirect Coombs test; 2 step process that measures anti-RBC antibodies in the SERUM
   - Used mainly in blood blanking; cross-matching, blood typing, Ab detection, Ab identification

Question 129

1. What occurs when
   - blood group O receive A,B or AB cells?
   - blood group A receive from B
   - blood group B receive from A
2. What are the clinical symptoms (4)
   - temp? GI? Pain? BP?

Answer 129

1. Transfusion reaction (Type II hypersensitivity)
   - Group O is universal donor
   - Group AB is universal recipient
   - group A only receive from A and O
   - group B only receive from B and O
   - group O only receive from O
2. Clinical symptoms
   - fever
   - hypotension
   - nausea and vomiting
   - back and chest pain

Question 130

1. Identify condition

• DRAMATIC Type II reaction 
• Called erthroblastosis fetalis 
• Antigen present on the surface of the red
cell
 Called rhesus (RhD)
 Occurs in a SECOND PREGNANCY of
women who is RhD(-) and has RhD (+) baby

2. Identify clinical symptoms and lab findings
   - bilirubin? Liver? Spleen? Test?
3. What is treatment option?
   - is it a one time treatment?

Answer 130

1. HEMOLYTIC DISEASE OF THE NEWBORN
2. • Elevated bilirubin
   • large liver and spleen
   • petechiae
   • POSITIVE direct Coombs test
3. Treatment; ANTI-D
   • Inject Rh(-) mothers with preformed anti-RhD (given at
   28 weeks gestation or within 3 days of potential exposure from miscarriage, trauma, or delivery)
   • These abs destroy RhD(+) fetal cells in maternal circulation
   • Repeat each pregnancy

Question 131

1. Identify the type II hypersensitivity condition

• Patients produce anti-RBC antibodies
• Can cause hemolysis of RBCs
• Positive direct Coombs

2. • target antigen; proteins in intercellular junctions of EPIDERMAL cells (epidermal Cadherin)
   • Mechanism; antibody-mediated activation of proteases, disruption of intracellular adhesions
   • Autoimmune blistering disease; SKIN VESICLES (bullae)
   • *WHAT DOES immunofloresece show?

Answer 131

1. AUTOIMMUNE HEMOLYTIC ANEMIA (AIHA)
2. PEMPHIGUS VULGARIS
   - antigen is fixed tissue antigen
   - IgG antibodies
   - Rare disease of skin & mucous membranes; Causes blisters all over the body
   - Autoantibodies against intercellular cement substance of skin & mucous membranes
   * *SEPARATION of EPIDERMAL LAYERS in skin or epithelial cells in mucosa
   * *Immunofluoresence show epidermis stains in fishnet pattern - LINEAR STAIN

Question 132

1. Identify the type II hypersensitivity

• Target antigen; noncollagenous protein in BASEMENT MEMBRANE of kidney glomeruli and lung alveoli
• mechanism; complement and Fc receptor-mediated inflammation
• Nephritis and lung hemorrhages

2. What test can you use to detect this?
3. treatment

Answer 132

GOODPASTURE SYNDROME
• Classic Type ll Hypersensitivity reaction
- Have anti-tissue antibody
- This causes activation of complement & recruitment of inflammatory cells
- Leads to: acute glomerulonephritis and pulmonary hemorrhage

2. Direct immunofluorscence with anti-gamma globulin antibody
   - patients IgG in a LINEAR intercellular pattern within the epidermis
3. Treatment
   - remove the anti-GBM antibody by PLASMAPHERESIS
   - treat patients with immunosuppressant drugs

Question 133

1. Identify the type II hypersensitivity condition

• Target antigen; streptococcal cell wall antigen - antibody cross reacts with myocardial antigen
• mechanisms; inflammation, macrophage activation
• myocarditis, arthritis

2. Clinical presentation

Answer 133

1. ACUTE RHEUMATIC FEVER
   - cross reactivity with antigen from infectious agent
2. • Follows a throat infection with group A streptococcus (S. pyogenes)
   • Clinical symptoms present about 2-4 weeks following onset of infection
   - Cardiac manifestations: chest discomfort, new or changing murmurs
   - Migratory arthritis
   - Immunologic features; Antibody to streptococcal cell wall may cross-react with cardiac antigens, “Molecular mimicry”

Question 134

1. Identify the type II hypersensitivity condition

• target antigen; intrinsic factor of gastric parietal cells
• Mechanism; Neutralization of intrinsic factor, decreased absorption of vitamin B12
• Abnormal erythropoiesis, anemia

Answer 134

PERNICIOUS ANEMIA
• B12 deficiency anemia, which is needed for RBCs
• Vitamin B12 must be joined with intrinsic factor
to be absorbed
 Patients produce antibodies to intrinsic factor (IF)
A second component of the disease process is parietal cell injury and a decline in IF production
Lack of intrinsic factor results in abnormal erythropoiesis and anemia

Question 135

What 2 disease (Type II hypersensitivity) are associated with antireceptor antibodies and how?

Answer 135

1. Myasthernia Gravis (decreased activity )
2. Grave’s disease (increased activity)

• Antireceptor Ab binds to receptor
• Impairing function; increased or decreased activity

Question 136

1. Identify type II hypersensitivity

• Target antigen; Acetylcholine receptor (downregulated)
• Mechanism; antibody inhibits acetylcholine binding, down modulates receptors
• Muscle weakness and paralysis

**WHAT IS major source of illness that leads to death?

Answer 136

1. MYASTHERNIA GRAVIS

• Autoimmune neuromuscular disease
• Get muscular weakness
• First see in drooping eyelids (PTOSIS)
• RESPIRATORY PROBLEMS - Major source of illness & can lead to death

Question 137

1. Identify type II hypersensitivity

• target antigen; TSH receptor
• Mechanism; Antibody-mediated stimulation of TSH receptors
• HYPERTHYROIDISM

**Trifecta of presentation?

Answer 137

GRAVE’S DISEASE

• Autoimmune thyroid disease
• Hyperthyroidism (heat intolerance, anxiety)
• Exopthalmos
• Myxedema

Graves’ Disease: Anti- TSH receptor antibody stimulates (binds) receptor, mimicking action of TSH, inducing continuous
release of T3 and T4

Question 138

Identify various treatment options of type II hypersensitivity

Answer 138

• Depends on specific disease
• In general can be divided into various therapies for the majority of disease processes including:
- Symptomatic treatments (e.g. ANTICHOLINESTERASE agents for
myasthenia gravis, BETA BLOCKERS and THYONAMIDES for Grave’s disease)
- Rapid immunomodulating treatments (PLASMAPHERESIS and
INTRAVENOUS IMMUNE GLOBULIN)
- Chronic IMMUNOSUPPRESSIVE agents [systemic steroids (which can also be used for acute treatment), other non-steroid immunosuppressants such as azathioprine, mycophenolate mofetil, and cyclosporine among others]

Question 139

Identify the general mechanisms of type III hypersensitivity

• involve what complex
• complex activate what? Which attract what to site?
• what does this cause?

Answer 139

Type III

• Involve IgM or IgG antibodies that react with soluble antigens to form immune complexes that are deposited in tissues
• Consequnce; complement and Fc mediated inflammation result in TISSUE DAMAGE
• *inflammation occur as result of neutrophils attracted to site
• *Type III reactions can be systemic or localized

**Immune complex deposition - platelet aggregation - microthrombus formation

Question 140

1. In type III, do immune complexes trigger increase or decrease in vascular permeability? How?
2. What are the favored sites for deposition of immune complexes? (5)
3. Identify they various antigen types (4)

Answer 140

1. Immune complexes is a trigger for INCREASING VASCULAR PERMEABILITY
2. • Kidney
   • Joints
   • small vessels
   • heart
   • skin
3. Antigen types
   - Infectious agents
   - Innocuous substances
   - self antigen
   - Persistence of antigen facilitates immune complex formation

Question 141

1. **What makes immune complexes deposit?
   - is larger or small the most pathogenic? Why or why not?
2. What are other variables that make immune complexes deposit (3)

Answer 141

1. SIZE
   - large/medium immune complexes are cleared and fix complement
   - most pathogenic; small ICs in Ab excess; small immune complex is most problematic because it DOES NOT FIX complement and are not cleared from circulation
2. A. Charge of immune complex
   B. Class of immune complex
   C. Antigen characteristics

Question 142

Identify the type III sensitivity

• PROTOTYPE immune complex disease
  • Antigen-antibody complexes from in circulation and
  deposit in tissues
  • Complement levels in serum decrease due to activation
  • Eventually excess (free) antibody limits formation of complexes

**Identify clinical manifestations that begin 1-2 weeks after first exposure

**Identify the pathologic lesions based on locations

Answer 142

SERUM SICKNESS; being 1-2 weeks after first exposure

• rash
• fever
• arthralgia or arthritis

**Antibodies to foreign proteins are produced and 1-2 weeks later, antibody-antigen complexes form and deposit in tissues - complement activation - inflammation and tissue damage

• *Pathologic lesions
• lesion in vessels; vasculitis
• lesion in kidney; glomerulonephritis
• lesion in joints; arthritis

Question 143

What is the difference in the immunofluorescence pattern between type II and type III hypersensitivity

Answer 143

Type II

• circulating antibody to tissue fixed antigen
• LINEAR immunofluorescence pattern

Type III

• circulating immune complexes
• deposition in tissues; LUMPY-BUMPY immunofluorescence pattern

Question 144

Identify type III conditions

1. • Repeated antigen exposure
   - Results in formation of immune complexes which deposit in many tissues
   - See in many autoimmune diseases such as rheumatoid arthritis & systemic lupus erythematosus
2. • caused by drug-specific immune complexes
   • Small drug molecules may serve as haptens that bind to serum proteins → then develop antibody response either to the hapten or the hapten- protein conjugate
   • *what drugs in particular?

Answer 144

1. CHRONIC IMMUNE COMPLEX DISEASE
2. Serum sickness - Drug reactions
   - a type of serum sickness caused by hypersensitivity to an IV injection of drug
   - Particualrly ANTIBIOTICS; penicillin mostly implicated although many drugs have been associated with these reactions

Question 145

Identify type III hypersensitivity conditions

1. Autoimmune disease characterized by chronically inflamed synovium
   * *what is the rheumatoid factor?
2. Chronic inflammatory disease targeting mainly
   joints, kidneys, heart, skin and lung → systemic
   autoimmune disease
   **what are the immunologic features?

Answer 145

1. RHEUMATOID ARTHRITIS
   - IgM which has specificity for determinants on the Fc portion of the patient’s own IgG (which in this case is the antigen)
   - the IgM antibody is called RHEUMATOID FACTOR and is deposited in joints
2. SYSTEMIC LUPUS ERYTHEMATOSUS (SLE)
   Immunologic features;
   - autoantibodies to multiple nuclear antigens, including DsDNA (immune complex deposition so much because DsDNA is everywhere in the body)
   - Antigen/antibody complexes damage tissues by activating complement and by engaging Fc receptors on immune cells expressing these receptors

Question 146

Identify type III condition

• Associated with infections with group A streptococcus
• Immunologic features
- Immune complexes deposit in the lipid bilayer of
the glomerular basement membrane
- Activation of the classical complement pathway → damage to basement membrane
• Abrupt onset of symptoms 1-4 weeks after infection → dark or smoky-colored urine

**What test can Dx this condition?

Answer 146

POST-STREPTOCOCCAL GLOMERULONEPHRITIS

Test; Direct Immunofluorescence with anti-gamma globulin antibody

• lumpy bumpy (granular) deposition of IgG, IgM and C3 in peripheral glomerular loops
• Lumpy bumpy (granular) or starry scar immunofluorescence

Question 147

Identify type III

• localized type II reaction
• Skin reaction which shows classic findings of Type III reaction
• Antigen injected intradermally in the presence of preformed antibody
• *present with vaccinations

Answer 147

ARTHUS REACTION

• antibody-antigen complexes that fix complement are deposited in the walls of small blood vessels which cause; acute inflammation, infiltration of neutrophils and localized skin necrosis
• Few hours after injection, start seeing some reaction in skin (peaks at 4-10 hours, get area of tissue necrosis)
• occurs in antibody excess
• Has been reported with tetanus, diphtheria and hepatitis B vaccines

Question 148

How do you measure immune complexes

Answer 148

1. Measure levels of complement
2. Will be decreased with active deposition of immune complexes
   - simple test
   - readily available
   - indirect measure
3. Direct method
   - obtain tissue biopsy
   - look for fibrinoid necrosis and other findings
   - can perform immunofluorescence to look for immunofluorescence to look for immune complex deposition

Question 149

Identify treatment of Type III hypersensitivity (2)

Answer 149

1. Antigen avoidance
2. Immunosuppression; for reactions against self antigens; systemic steroids and other non-steroid immunosuppressants such as AZA (Azathioprine), mycophenolate mofetil, cyclosporine

Question 150

1. Identify Hypersensitivity

• Originally used to describe all hypersensitivity reactions which took more than 12 hours to develop
• Also called Delayed Type Hypersensitivity (DTH)
• Includes classic DTH reactions & T-cell mediated cytotoxic reactions
• Transferred by cells, not serum

2. What immune cells initiate this response? What cells mediate?
3. What cells mediate direct killing?

Answer 150

1. Type IV Hypersensitivity (cell-mediated)

• Reaction is initiated by antigen specific Th1 cells
• activate T cells and macrophages are the major cellular mediators of these reactions
• cytokines are very important in amplifying and continuing the response

2. Mostly involves responses initiated by antigen-specific Th1 cells resulting in inflammation mediated by MACROPHAGES
3. CD8+ T cells - mediate direct killing

Question 151

1. What are the hallmarks of a type IV reactions? (4)
2. What process is responsible for the following;
   A. Important in killing viruses and tumor antigens
   - destroy target cells
   - CD8+ cells
   B. Lysis of target cells
   - specific
   - dependent on Class I HLA antigens
3. What are the target antigens of type IV (3)

Answer 151

1. • the delay in time required for the reaction to develop to re-exposure to antigen
   • the recruitment of MACROPHAGES (as opposed to neutrophils)
   • extensive tissue damage
   • association with cytokines
2. T-cell mediated cytotoxicity
3. A. Innocuous environmental antigens; often seen in contact dermatitis
   B. Self antigens; associated with autoimmune disease
   C. Intracellular pathogens that are hard to clear; like mycobacterium

Question 152

Give examples of antigens (microbial or innocuus**) that induce delayed type hypersensitivity

Answer 152

1. Innocuous
   - Nickel
   - hair dye
   - URUSHIOL (found in POISON IVY)
2. Microbial
   - Mycobacterium TB
   - Herpes simplex
   - Mycobacterium lepra
   - Smallpox
   - listeria monocytogenes
   - measles virus
   - brucella abortus
   - Candida albicans
   - histoplasmosis capsulatum
   - cryptococcus neoformans

Question 153

1. DO infections disease manifest delayed hypersensitive? Give examples of infectious agents and diseases

Answer 153

1. A. Many due to infectious agents; mycobacteria, Protozoa and fungi

B. Diseases; TB, leprosy, leishmaniasis, listeriosis, deep fungal infections, sarcoidosis and parasitic infections

C. Viral hepatitis

Question 154

1. Identify condition

• Allergen is placed in contact with the skin
• Area of crusting with erythema at the site of contact
with the allergen
• Reaction is maximal at 48 hours
• Induced by haptens such as nickel and chromate
• Bind to normal skin proteins and become antigenic
• Commonly caused by rubber, poison oak & ivy

2. What is target organ? What are antigen substances?
3. Identify histologic features
4. What is patch test

Answer 154

1. CONTACT HYPERSENSITIVITY (Type IV)
2. • Sensitizing substance is often a hapten that complexes with skin
   proteins (carrier)
   • Target organ is skin
   • Antigens-substances like nickel, poison ivy, drugs etc.
3. • langerhan’s cells are the principal antigen-presenting cells
   • cytokines are crucial in mediating and continuing the reaction
4. Positive skin test to Nickel; Patch test
   - put antigens on your back and leave it for 48 hours
   - test to detect type IV reactions

Question 155

What are the tests for decking type IV reactions

- which can you used for PPD? What does the test tell you?

Answer 155

1. A. Patch test
   - in vivo test to assess person’s reactivity to contact antigens
   - sensitize antigen by placing on the skin and covered with a dressing
   - examined 2-3 days later

B. DTH skin test (PPD)

• in vivo test assess immunologic memory for specific antigens
• antigen injected INTRADERMALLY
• reaction peaks at 48-72 hours
• positive run means person has been sensitized
• A non reactive person is called anergic

**Positive DTH skin test only tells you that there are sensitized T cells present - gives no information on whether the disease is active

Question 156

1. • Classic DTH response
   • Occurs as an erythematous indurated lesion
   • Maximal 48-72 hours after challenge with tuberculin
   antigen in a sensitized individual
   • Antigen applied intradermally
2. • In countries where you are at increased risk for TB
   • test for release of interferon gamma after incubation with TB antigen
   • *what are advantages vs disadvantages of this test?
3. • Clinically significant form of DTH
   • Results from antigen persisting in a macrophage
   • Epithelioid cells & multinucleated giant cells

Answer 156

1. Tuberculin-type Hypersensitivity
2. TB test from blood; IGRA (Interferon-gamma release assays)
   A. IGRA disadvantage
   - Does not differentiate past from present infection
   - It only demonstrates the presence of sensitized T cells
   - Need to correlate with clinical presentation to determine if the disease is active
   - error in collecting/tranporting blood specimens will decrease accuracy of IGRA
   - there is limited data on the use of IGRAs to predict who will progress to TB disease in the future
   - may be expensive
   - limited data for use in; children younger than 5, recently exposed to TB, immunocomprised persons, serial testing

B. IGRA advantages

• requires a single patient visit to conduct the test
• results can be available within 24 hours
• Does not boost responses measured by subsequent tests
• Prior BCG vaccine does not cause a false-positive IGRA test - seen only with in vivo DHT PPD testing

C. Granulomatous Hypersensitivity

Question 157

1. • IL 12/APC drives TH1
   • IFN gamma activates macrophages
   - Ability to kill & phagocytose is increased
   - Produce TGF-beta, increase fibrosis
   • TNF –alpha: acts on vessels to increase cells in area
   (Turn into a feedback mechanism)
2. • core of epithelioid cells & macrophages, often with giant cells
   • may be central zone of necrosis, surrounded by cuff of lymphocytes with accompanying fibrosis

** what disease have granulomas?

Answer 157

1. Granuloma formation
2. Granulomatous hypersensitivity (Type IV)

**Infectious Disease manifesting delayed hypersensitivity
A. Many due to infectious agents; mycobacteria, Protozoa, fungi
B. Diseases; TB, leprosy, leishmaniasis, listeriosis, deep fungal infections, sarcoidosis and parasitic infections

Question 158

1. What is the inability to react to common skin antigens called?
   - how do you test this?
2. Identify diseases associated with #1

Answer 158

1. ANERGY
   • This is tested by performing DTH skin tests, using a
   panel of commonly encountered antigens
   • Confirm negative using higher ag concentration
   • For PPD, include positive control
   - Exclude false negative PPD
2. • Congenital immunodeficiencies; secondary or acquired immunodeficiency such as AIDS
   • Autoimmune diseases: rheumatoid arthritis
   • Malignancies: Hodgkin’s disease, Lymphoma, Chronic lymphocytic leukemia
   • Sarcoidosis
   • Infections: Influenza, Mumps, Measles, TB, Leprosy, & others

Question 159

What are treatment options for type IV hypersensitivity (3)

Answer 159

1. Antigen avoidance
2. Anti-inflammatory drugs
3. Immunosuppression; for reactions against self antigens

Question 160

1. What are the 2 main classifications of gram positive bacteria
2. Give further classification of #1
3. • where is staphylococcus vs streptococcus classified under?
   • give further classification of staphylococcus
4. Give further classification of streptococcus

Answer 160

1. Gram positive
   A. Cocci
   B. Rods
2. A. Rods;
   - aerobic; bacillus (spores), nocardia (branching), listeria (motile), corynebacterium
   - anaerobic; clostridium (spores), actinomyces (branching)

B. Cocci;

• clusters (catalase +); STAPHYLOCOCCUS
• pairs/chains (catalase -); STREPTOCOCCUS

3. A. Staphylococcus (catalase +); coagulate (+) e.g staphylococcus aureus
   B. Staphylococcus (catalase +); coagulate (-) e.g S. Epidermidis (novobiocin S), S. Saprophyticus (novobiocin R)
4. Streptococcus (catalase -); alpha hemolysis (partial, green), beta hemolysis (complete, clear), gamma no hemolysis
   A. Partial hemolysis (alpha); Strep pneumonia (optochin S: capsule), viridans streps (optochin R : no capsule)
   B. Complete hemolysis (beta); Strep pyogenes (bacitracin S), Strep agalactiae (bacitracin R), enterococcus
   C. no hemolysis (gamma); enterococcus, peptostreptococcus

Question 161

1. What is the causative agent of pneumonia
2. What is the lineage
3. Is this bacteria part of normal flora? If it is why will it cause disease?
4. Identify to major ways to classify the genus of this bacteria?

Answer 161

1. Streptococcus pneumonia (capsule;optochin S - partial alpha hemolysis, catalase - pairs/chains, cocci, gram positive)
2. Lineage - Firmicutes
3. Streptococci
   - it is part of normal flora
   - However it can cause disease; strep throat, meningitis, pneumonia, baceremia, brain abcess, endocarditis, gangrene
4. the genus is classified on the basis of HEMOLYSIS (partial, complete or no) and SEROLOGIC SPECIFICITY

Question 162

1. Identify classification type
   - Blood agar plates differentiate streptococci species based on hemolysis pattern
   • Beta-hemolytic: complete hemolysis
   • Alpha-hemolytic: partial hemolysis
   • Gamma-hemolytic: no hemolysis
2. • Based on cell wall carbohydrate antigens
   • Human pathogens largely Groups A - D
   • One group, one species (Group A = S. pyogenes)
   • One group, multiple species (Group D strep)
   • One species, multiple groups
   (S. dysgalactiae→ Group C, G )
   **what is problem with this classification?

Answer 162

1. Hemolysis pattern
2. Lancefield classification
   * *Problem is that some groups can have multiple species e.g enterococcus

Question 163

** Identify general characteristic of streptococcus

1. Gram class
2. Clusters? Chains? Pairs?
3. Motile or not?
4. Oxygen needed or not?
5. Catalase?
6. Nutrition requirement?

**
Can people that have CGD be infected with streptococcus? Why or why not?

Answer 163

• *
  1. Gram positive (+ve)
  2. Cocci arranged in PAIRS OR CHAINS
  3. NON-MOTILE
  4. Facultative ANAEROBIC OR CAPNOPHILIC
  5. Catalase NEGATIVE (can;t breakdown hydrogen peroxide)
  6. Nutritional requirement; complex, need blood or serum enrich media for isolation

**
CGD - CHRONIC GRANULOMATOUS DISEASE (phagocytic defect)
• genetic mutation - do not have high catalase, so ONLY CATALASE POSITIVE CAN CAUSE PROBLEM
• STREPTOCOCCUS CANNOT CAUSE DISEASE - no strep throat in these patients
• They have lots of other bacteria and fungi infections (staph etc) but nothing from streptococcus. NOT SUSCEPTIBLE TO STREPTOCOCCUS INFECTIONS

Question 164

1. Based on lancefield classification of streptococcus, give an example of Group A?
2. Identify characteristics of Group A
   - gram class? Chain or clusters?
   - need oxygen?
   - capsule or no capsule?
   - hemolysis pattern
   - how may types of M-proteins
   - what other protein

**why do you get strep throat repeatedly

Answer 164

1. Group A; Streptococcal pyogenes

2. Xters 
• Gram+ve, cocci in chain 
• Facultative anaerobe 
• Capsule (hyaluronate) - VIRULENT 
• β-hemolytic on blood agar 
• M-proteins (150 types), auto-antibodies 
• F -protein bind fibronectin

**
• You get strep throat repeatedly because you have 150 different types of M-proteins; important becuase it is associated with auto antibodies

Question 165

Identify a major virulence factors of group A streptococcus that - lyse blood cells and plates, stimulate release of lysosomal enzymes

1. (oxygen-labile): Lyses leukocytes, platelets, and erythrocytes; antigenically related to oxygen-labile toxins produced by other Gram-positive bacteria such as S. pneumonia, clostridium tetani, Bacillus cereus and Listeria monocytogenes; immunogenic, indicating a recent GAS infection (ASO test), but test not commonly performed
2. (oxygen-stable): Lyses leukocytes, platelets, and erythrocytes; stimulates release of lysosomal enzymes; β-hemolysis; nonimmunogenic

Answer 165

1. Streptolysin O
2. Streptolysin S - the S indicates serum stable.

**These 2 toxins are the main causes of hemolysis

Question 166

Identify virulence factors of group A strep that aid in bacterial spread

1. Four immunologically distinct forms (A,B, C,D)
   - what is an important marker?
2. Catalyze activation of palsmin to lyse blood clots

Answer 166

1. DNase: Four immunologically distinct forms (A,B,
   C,D)
   • (Anti-DNase B) Important marker of cutaneous
   group A streptococcal infections, particularly useful
   for those who fail the ASO test.
   • Depolymezes cell free DNA in pus (reduction of
   viscosity); contribute to spread from local site
2. Streptokinase; promotes bacterial spreads into tissues by breaking down blood clots

Question 167

Give 6 examples of suppurative streptococcal disease

• strep throat name?
• red rash on trunk and extremities? Strew berry tongue?
• purulent with crusting
• number causative agent of what infection?
• slapped cheek rash
• gangrene on skin

Answer 167

1. Pharyngitis: strep throat (exudate on tonsils)
2. Scarlet fever: complication of pharyngitis when bacterial strain is lysogenized by bacteriophage that produce exotoxins (red rash on trunk, strawberry tongue)
3. Skin infections: Impetigo (Streptococcal Pyoderma): purulent with crusting
4. Cellulitis: (#1 causative agent) GAS cellulitis infects wounds (burns, trauma, IV drug abuser injection site)
5. Erysipelas: acute infection of the skin. mostly of the face “slapped cheek” rash, lymph node enlarged.
6. Necrotizing faciitis; Flesh-eating rapidly spreading gangrene of skin and fascia. Starts with trivial skin infection but is rapidly fatal due to multi organ failure

Question 168

The following are under what disease class

• No Group A streptococcus present, Immunologic, or
autoimmune disease
• AGN (Acute Glomerular Nephritis), PSGN or APSGN • Acute inflammation of the renal glomeruli with edema,
hypertension, hematuria and proteinuria.
• Post-pharyngitis caused by M types 1, 4, 12, and 25 or
post-skin caused by M types 2, 42, 49, 56, 57 and 60
(skin). These strains collectively known as
nephritogenic.
• Symptoms: facial edema, blood in urine(smoky urine)

Answer 168

Nonsuppurative Streptococcal Disease - AGN (acute inflammation of renal glomeruli)

• Immune complex formation deposit on the basement membrane of glomeruli and cause problem - cause inflammation? - complement and phagocytosis
• AUTOIMMUNE DISEASE - TYPE III hypersensitivity (antigen-antibody complex on basement membrane)

**occurs most commonly in children by nephritogenis strain

Question 169

Identify condition

• Pancarditis (endo, peri, and myocarditis)
• No Group A streptococcus present
• Post pharyngitis only
• Due to cross-reactivity of anti-M protein antibody
with human cardiac tissue
• Symptoms: migratory arthritis, subcutaneous
nodules, carditis and erythema marginatum

***IDENTIFY 3 Classic clinal presentation

Answer 169

ACUTE RHEUMATIC FEVER (ARF)
• May proceed to Rheumatic fever.

CLASSIC PRESENTATION

1. Subcutaneous nodules
2. ASCHOFF BODIES (antibodies attack)
3. Erythema marginatum

Question 170

It has been hypothesized that certain types of pediatric neurobehavioral conditions may follow streptococcal infections.

**what is this called

**what is the Association with GAS

Answer 170

PANDAS; Neurobehavioral disease

Post-streptococcal Autoimmune, Neuropsychiatric Disorders Associated with Streptococci (PANDAS) is a term used to describe a subset of children whose symptoms of obsessive-compulsive disorder (OCD) or tic disorders that are exacerbated by GAS infection.

The hypothesized association between PANDAS and GAS is controversial, as is the limitation of the diagnosis exclusively within the pediatric age group.

Question 171

1. What is the source and transmission of GAS (group A strep)
2. How do you diagnose

Answer 171

1. • Normal flora of skin and oropharynx
   • Cause infection upon penetration of tissue
   • Transmission: person to person
2. • Microscopy:
   • Antigen detection: Throat swabs
   • Antibody detection: ASO test in rheumatic fever
   • Culture:blood agar or specialized selective agar
   • Treatment: sensitive to penicillin. Oxacillin or vancomycin (in mixed culture)
   **Most group A strep are sensitive to penicillin and bacitracin

Question 172

Identify group of streptococcus based on lancefield classification

• Gram-positive
• Cocci in pair
• Capsule
• CAMP test positive
• β – hemolytic (1-2% strains non-hemolytic)
• threat to infants infected perinatally
• also responsible for Post-partum endometritis
(especially following C section)

Answer 172

Group B Streptococcus (GBS) - S. agalactiae

Question 173

1. Identify source and transmission of GBS
2. Virulence factors
3. Early vs late onset neonatal disease
4. What is acquired via wound inflected during parturition? Symptoms?
5. What test can identify GBS
6. Treatment

Answer 173

1. • Normal flora of GI tract and vagina
   • Vertical transmission: either at birth or via ascension in utero **GBS can be transmitted to baby
2. • Capsule: resist phagocytosis
   • Sialic acid: capsular component, inhibit alternate pathway of complement
3. A. early onset; begins within 7 days of birth
   - acquired in utero or at delivery
   - most common in premature infants
   - high mortality rate
   - symptoms; bacteremia, pneumonia, meningitis
   B. Late onset; begins 1 week to 3 months after birth
   - acquired postpartum
   - low mortality rate (<20%)
   - symptoms; bacteremia, meningitis
4. POSTPARTUM SEPSIS
   Symptoms; postpartum endometriosis, fever and chills, wound infection, possible UTI
5. CAMP-test; CAMP factor produced by GBS that enhances β -hemolysis of S.aureus
6. Treatment
   o PENICILLIN G alone or in combination with an Aminoglycosides
   o Passive immunization in serious cases

Question 174

Identify bug

• Gram positive 
• Cocci in pair or short chain 
• Capsule 
• CAMP test negative 
• Bile solubility- positive 
• a-hemolytic (aerobically) 
• b-hemolytic (anaerobically) 
• Genome diversity: 20% of DNA sequences different, still the
same species. 
• Catalase –negative; Grow best in 5% CO2, Requires a source of catalase (blood) to grow on agar, Chronic granulomatous disease-resistance to SP

Answer 174

STREOTOCOCCUS PNEUMONIAE

HIGH YIELD - strep pneumonia on step
• Have CAPSULES so cause disease (virulent)
• CGD disease (chronic granulomatous disease) is RESISTANT to streptococcus (pyrogens and pneumonia

Question 175

Identify virulence factors of streptococcus pneumonia (5)

Answer 175

• Capsules: resist phagocytosis; >90 serotypes
identified, the major protective antigen.
• Robust biofilm formation.
• IgA proteases cleaves IgA into Fab and Fc
fragments
• Adhesins: mediates attachment of S. pneumonia to epithelial cells
• Pneumolysin: destroys the ciliated epithelial
cell

Question 176

1. Identify 4 infections caused by streptococcus pneumonia
2. How do you diagnose #1 (4)

3.

• what will optochin sensitivity show?
• explain quelling reaction?
• hemolytic strep?

Answer 176

1. • Lobar pneumonia (#1 causative organism in adults and in sickel cell disease)
   • Meningitis (#1 causative agent in adult meningitis)
   • Sinusitis (#1 causative organism)
   • Otitis media (#1 causative organism)

2. 
• Microscopic examination: Gram stain 
• Quellung Reaction: Polyvalent anti-capsular antibodies are mixed with the bacteria: increase in refractive mass around the bacteria
• Bile sensitive 
• Optochin sensitive

3. Optochin sensitivity
   • No growth means sensitive
   • Growth means resistant
4. Quellung reaction
   • Mix bacteria with antibody
   • Tells you that A) bacteria still produce capsule (virulent). B) bind to cell wall?
5. Strep pneumonia are hemolytic

Question 177

***How do you make ANTIMICROBIAL vaccine

Answer 177

• Bacteria with CAPSULE is virulent (cause disease)
• Protective antibody is IgG
◦ Cross link diphtheria toxoid conjugated with capsular polysaccharide for strep vaccine (ANTIMICROBIAL VACCINE)
◦ Most effective defense we have against bacteria is phagocytosis? So polysaccharide coats it so that phagocytosis can occur?
• T cells not produce cytokines that cause CLASS SWITCHING

Question 178

How do you treat streptococcus pneumonia

Answer 178

• Penicillin • Vancomycin combined with ceftriaxone in penicillin
allergy
• Three vaccines approved (USMLE):
- PPSV-23 (adult vac): 19-64 yr old with chronic and
immunosuppressive condition, and people of 65 yr old or
older should be routinely immunized.
- PCV-7 (children vac): Age of 2-23 months to prevent
invasive infections and selected children of aged 24-59
months
- PCV-13 (new children vac): recently approved for all
children as part of four doses series at 2, 4, 6, and 12-15
months old
**vaccine don’t protect against all 90 types that why you still get pneumonia

Question 179

Identify various streptococcus infections

1. GAS
2. Suppurative
3. Non-suppurative
4. GBS
5. Strep pneumo
6. Enterococcus

Answer 179

1. GAS: Gram+ve, catalase-ve, doesn’t like oxygen,
   hemolysis, capsule, M proteins, C5a peptidase,
   extracellular enzymes; GBS: capsule.
2. Suppurative: Pharyngitis, Scarlet fever, Impetigo,
   Cellulitis, Erysipelas
3. Non-supparative: PSGN, ARF, PANDAS
4. GBS: neonatal meningitis and sepsis, CAMP testing,
5. Strep Pneumo: polysaccharide, vaccine, T-cell
   independent, bile, IgA protease, lobar pneumonia,
   meningitis, sinusitis, Otitis Media
6. Enterococcus, antibiotic resistance, normal flora, VRE,
   ICU, and hospital-acquired UTI

Question 180

Identify species

Normal flora of the large bowel and feces; Antibiotic resistance is common; Most common cause of nosocomial infections, particularly in ICU;

Answer 180

ENTEROCOCCUS

Question 181

Identify physiology and structure of enterococcus

• gram class
• need oxygen?
• what group?
• catalase?
• bacitracin?
• hemolysis
• nutritition?
• bile?
• what organic compound can they hydrolyze?

Answer 181

ENTEROCOCCUS
• Gram positive cocci in pairs or short chain
• Grow both aerobic and anaerobic in a broad range of temp (10-45 C)
• Group D cell wall antigen: Teichoic acid, not good marker
for classification
• Catalase negative
• Bacitracin resistant
• Variable hemolysis
• Can grow in presence of 6.5% NaCl
• Can tolerate 40% bile salt
• Can hydrolyze esculin

Question 182

What is source and transmission of enterococcus

Answer 182

• Enteric bacteria
• Found in large intestine and genitourinary tract
• Human infections originate from patients bowel flora

Question 183

Identify the virulence factors of enterococcus

Answer 183

• Aggregation substance
• Carbohydrate adhesins
• Cytolysin ; inhibits gram positive bacteria and induce local tissue damage
• Gelatinase

**helps in colonization

Question 184

What 3 antibiotics is enterococcus resistant to?

**what type of intrinsic

Answer 184

Intrinsic resistance

1. AMINOGLYCOSIDES resistance
   - coded by conjugation plasmids or transposons
2. VANCOMYCIN resistance
   - most common in E.faecium
   - encoded on a 3 gene cluster (vanHAX) within a transposon
   - the first 2 gene products mediate production of the depsipeptide rather than the d-Ala-d-Ala
   - the 3rd product is a dipeptidase which depletes d-Ala-d-Ala

• beta-lactamase production on plasmid
  3. TRIMETHOPRIM-SULFAMETHOXAZOLE resistance

Question 185

What is diagnosis and treatment of enterococcus

Answer 185

• Biochemical test: Resistance to optochin
• Do not dissolve when exposed to bile
• Ampicillin can be used for sensitive strains
• Combination of an aminoglycoside and vancomycin for resistant strains

Question 186

Identify bacteria

• A major part of normal flora of the mouth and teeth. • Identification: a-hemolytic, resistance to optochin
  and no Lancefield antigens
  • Groups C and G streptococci- non rheumatogenic
  but otherwise spectrum of infections like group A
• *This bacteria is the number 1 causative agent of what infection?
• *What is the treatment

Answer 186

VIRIDANS STREPTOCOCCUS

• *Number 1 causative agent of SUB-ACUTE ENDOCARDITIS
• central role in dental carries
• *Treatment
• penicillin and antibiotic prophylaxis

Question 187

Staphylococcus aureus is a leading cause of what types of infections (5)

Answer 187

• Skin and soft tissue infections
• Bacteremia
• Endocarditis
• Bone and joint infections
• Pulmonary infections

Question 188

What are the general characteristics of staphylococcus

• gram class
• motility?
• need oxygen?
• catalase? Coagulate?
• nutrient to grow?
• genus?

Answer 188

- Gram positive: most resistant of the
non-spore formers to adverse condition: 
- Non-motile 
- Facultative anaerobic 
- Catalase +; coagulase +/- 
- Can grow: medium containing 10% NaCl 
- Genus: 40 species; 16 are found on
humans 
- S. aureus (coagulase-positive) 
- CNS: S. epidermdis, and S. saprophyticus

Question 189

Identify the 3 species of staphylococcus based on;

1. Frequency of disease
2. Coagulate
3. Color of colonies
4. Mannitol fermentation
5. Novobiocin resistance

Answer 189

1. Frequency of disease
   A. S.aureus; common
   B. S. Epidermidis; common
   C. S. Saprophyticus ; occasional
2. Coagulate
   A. S.aureus; (+)
   B. S. Epidermidis; (-)
   C. S. Saprophyticus; (-)
3. Color of colonies
   A. S.aureus; bronze
   B. S. Epidermidis; white
   C. S. Saprophyticus; white
4. Mannitol fermentation
   A. S.aureus; (+) produce lactic acid
   B. S. Epidermidis; (-)
   C. S. Saprophyticus (-)
5. Novobiocin resistance
   A. S.aureus (-)
   B. S. Epidermidis (-)
   C. S. Saprophyticus (+)

**they are oppurtunistic pathogens - occur when your immune system is weak

Question 190

Identify the physiology and structure of staphylococcus

1. What helps in adherence, inhibit chemotaxin and phagocytosis
2. What protein is present in S.aureus only?
3. What is made of glycerol, ribitol?
4. Clumping factor
5. Identify enzymes

Answer 190

1. Capsule: more common in vivo. Helps in
   adherence, inhibiting chemotaxis,
   phagocytosis. More important in Coagulase
   negative strains
2. Protein A: S. aureus only
3. Techoic acid (TA): Glycerol TA (SE), Ribitol
   TA (SA)
4. Coagulase (clumping factor): S. aureus
5. Enzymes: Lipase, hyaluronidase, nuclease,
   beta-lactamase

Question 191

Identify bacteria

• Gram-positive, cluster-forming coccus
• Nonmotile, nonsporeforming facultative anaerobe
• Fermentation of glucose produces mainly lactic acid
• Ferments mannitol (distinguishes from S. epidermidis)
• catalase positive; coagulase positive
• golden yellow colony on agar
• normal flora of humans found on nasal passages, skin and
  mucous membranes
• pathogen of humans, causes a wide range of suppurative
  infections, as well as food poisoning and toxic shock
  syndrome

Answer 191

STAPHYLOCOCCUS AUREUS

Question 192

Identify structure in staphylococcus aureus

● Present on the surface of most S. aureus
strains. Belong to a group of adhesins called
Microbial Surface Components Recognizing
Adhesive Matrix Molecules (MSCRAMMS)
● It is covalently linked with the peptidoglycan
layer
● Unique affinity to bind Fc portion of IgG
● Protects : opsonization and phagocytosis

Answer 192

Protein A

** Unique ability to bind to Fc portion of immunoglobulin - protects opsonization and phagocytosis

Question 193

Identify structure in staphylococcus

● Cell wall-bound coagulase is the
clumping factor that belongs to MSCRAMM which adhere to the fibrinogen and fibrin.
● Coagulase binds to prothrombin,
together they become enzymatically active to initiate fibrin polymerization.
● Protects bacteria under fibrin mash

Answer 193

Clumping factor (Coagulase)
- S.aureus

Question 194

Identify staphylococcal toxins

1. Cytolytic toxins (hemolysins)
2. Exofoliative toxins
3. Enterotoxins
4. Toxic shock syndrome toxin

**which once’s are superantigens?

Answer 194

1. Cytolytic toxins (hemolysins)- alpha, beta, gamma,
   delta, Panton-Valentine [P-V] leukocidin
2. Exofoliative toxins (A+B): A phage encoded and heat
   stable; B plasmid mediated and heat labile.
3. Enterotoxins – Eight enterotoxins toxins (A to E, G to I)
4. Toxic shock syndrome toxin– 1 (TSST-1)

***Exfoliative toxins A and B, the enterotoxins, and
TSST-1 are superantigens.

Question 195

Identify component in staph aureus

● PVL is encoded on a mobile phage. More common in CA-MRSA
● Active against PMNs and Macrophages causing cell lysis.
● Makes S. aureus more resistant to phagocytosis.
● Necrotizing pneumonia, mortality rate reaching 60%.
● Airway bleeding, erythroderma and leucopenia, often caused by MRSA

Answer 195

Panton-Valentine Leukocidin (lyse leukocyte)

• straps aureus produces this toxin (leukocidin) against neutrophils.
• In an experiment, they depleted neutrophils in mice and 10 staph aureus killed the mice

Question 196

Identify 3 Staph aureus toxin-mediated diseases based on their clinical manifestations

1. Fever, hypotension, rash
2. Short incubation (< 6 hours), vomiting-predominant illness
3. Desquamating rash

Answer 196

1. Toxic shock syndrome
   PATHOGENESIS; TSST-1 (Toxic shock syndrome toxin-1) - superantigen that results in polyclonal T cell activation
   CLINICAL; Fever, hypotension, rash
2. Staph aureus food poisoning
   Pathogenesis; pre-formed heat stable Enterotoxins (can’t die even if you heat the food)
   Clinical; short incubation, vomiting (< 6 hrs)
3. Scalded skin syndrome
   Pathogenesis; exfoliative toxin
   Clinical; desquamating rash

Question 197

Identify the following SSTI (skin and soft tissue infections) that staph aureus can cause from benign to severe

Answer 197

1. Benign; impetigo, uncomplicated abcess
2. Severe; necrotizing fasciitis, pyomyositis

• *Rise of CA-MRSA in the 1990s
• *Most common pathogen in surgical site infections, cutaneous abscesses

Question 198

Identify the infection

• common sources are vascular catheter-related infections, skin infections and pulmonary infections
• most common distinction is complicated vs complicated infections which will impact prognosis and management (e.g antibiotic therapy duration) ?? Explain the diff

Answer 198

SAB (staphylococcus bacteremia)

• To be considered UNCOMPLICATED SAB:

• Patient does not have endocarditis
• There are no implanted prostheses
• Follow-up blood cultures drawn 2-4 days after the initial set are negative
• The patient defervesces within 72 hours of initiation of effective antibiotic therapy
• There is no evidence of metastatic sites of infection

• All other patients with SAB should be considered to have COMPLICATED SAB
- Complicated SAB → poor outcomes including death (SAB has ~20% 30-day mortality) and recurrence

Question 199

Identify infection

Proportion of these cases due to S. aureus is increasing
• Most common cause in the industrialized world (contrast with viridans strep in resource-poor regions)
• Compared to other causes, S. aureus is: More likely to be associated with intravenous drug use, healthcare contact,
more acute presentation, persistent bacteremia, intravascular device, strokes, and diabetes mellitus

**what is mortality

Answer 199

Staphylococcus aureus INFECTIVE ENDOCARDITIS (IE)

**Mortality with SA IE is higher than for other pathogens because they are more virulent

Question 200

S. aureus is the leading pathogen in all 3 major classes of bone and joint infections:

** what are the 3 major classes?

1. especially of long bones in children, vertebral infection in adults with bacteremia, and in association with diabetic foot ulcers
2. usually in patients with bacteremia
3. especially in the first month after implantation

Answer 200

Staphylococcus aureus Bone and Joint infections

1. OSTEOMYELITIS – especially of long bones in children, vertebral infection in adults with bacteremia, and in association with diabetic foot ulcers
2. NATIVE JOINT SEPTIC ARTHRITIS – usually in patients with bacteremia
3. PROSTHETIC JOINT INFECTIONS – especially in the first month after implantation

Question 201

Identify 4 pulmonary infections caused by staph aureus

Answer 201

1. VAP (ventilator associated pneumonia)
   - staph aureus in nose start to grow on tube and progress down to lungs
2. Post-viral pneumonia
3. CA-MRSA necrotizing pneumonia - young other wise healthy patients, high mortality rate
   - community acquired pneumonia
4. Emphyema

Question 202

Identify the key concepts in staphylococcus aureus treatment

Answer 202

** Treatment depends on site of infection

Key concepts;

1. Establish extent of infection
2. Drain pus (so abx can penetrate and kill pathogen)
3. Remove infected hardware (e.g ventilator tube, foley catheter)

Question 203

Penicillin becomes useless in treating spaph aureus infections due to resistance.

1. What test can you use to determine this?
2. What property of the bacteria mediates resistance?
3. What semisynthetic penicillin where developed?

Answer 203

1. Disk diffusion testing aka Kirby-Bauer Susceptibility Test
2. Plasmid control
   - Penicillin becomes useless in treating S. aureus infection because of resistance.
   - Beta lactamase is common, and under plasmid control (penicillin G, ampicillin, ticarcillin, piperacillin).
   - Resistance to tetracyclines, erythromycins, and aminoglycosides are also medicated by plasmids.
3. Semisynthetic penicillin were developed such as;
   - nafcillin and oxacillin (and methicillin),
   - Methicillin resistant Staph aureus (MRSA)
   - In contrast, Methicillin susceptible Staph aureus (MSSA)

Question 204

SA-MRSA

1. The mecA gene responsible for methicillin resistance is located where? (Chromosome or plasmid?)
2. What does the gene encode?
3. How many SCCmec types are there?
4. What is the treatment of MRSA***

Answer 204

1. On a mobile genetic element called STAPHYLOCOCCAL CASSETTE CHROMOSOME MEC (SCCmec)
   * *The resistance is carried on the CHROMOSOME not the plasmid
2. The gene encodes the protein PBP2a (penicillin binding protein 2a). PBP2a has a low affinity for beta-lactam antibiotics such as methicillin and penicillin. This enables trans-peptidase activity in the presence of beta-lactams, preventing them from inhibiting cell wall synthesis.
3. There are 12 different SCCmec types. Types I, II and III are
   associated with hospital-acquired infections and may encode
   genes that confer resistance to other antimicrobials as well.
   Type IV is found in community acquired MRSA (CA-MRSA),
   less resistant, but more transmissible in the United States.
4. Treatment of MRSA: Vancomycin. MIC: 2 ug/ml or less (sensitive); MIC: 4-8 ug/ml (intermediate) due to increased
   cell wall synthesis.
5. Vancomycin-resistant SA (VRSA; MIC: >16 ug/ml) due to
   horizontal gene transfer (transposon) from Enterococci to
   Staph (see vanHAX cluster above). A major concern
   worldwide.

Question 205

1. What are common antibiotics used to treat staphylococcus aureus infections
   - MSSA
   - MRSA
   * what agent is preferred in MSSA

Answer 205

**You can give 2 drugs together

• MSSA – β-lactam agents preferred
– Intravenous therapy for serious infections: nafcillin, oxacillin,
cefazolin – Oral therapy options - cephalexin, amoxicillin/clavulanate, dicloxacillin

• MRSA
– Intravenous therapy for serious infections: vancomycin,
daptomycin – Oral therapy options: linezolid, clindamycin,
trimethoprim-sulfamethoxazole, tetracyclines

Question 206

Identify the following staphylococcus aureus treatment options

1. Impetigo
2. Uncomplicated skin abcess
3. Uncomplicated bacteremia
4. Complicated bacteremia
5. Pneumonia
6. Infection of dwelling hardware if it is not removed

Answer 206

1. Impetigo
   Tx; topical antibiotics (mupirocin, retapamulin)
2. Uncomplicated skin abcess
   Tx; Incision and drainage - abx not necessarily required
3. Uncomplicated bacteremia
   - 1-2 weeks IV therapy from date of first negative blood culture (vancomycin of daptomycin for MRSA, cefazolin or nafcillin for MSSA)
4. Complicated bacteremia
   - 4-6 weeks IV therapy
5. Pneumonia
   - 7-21 days, depending on severity
6. Infection of dwelling hardware if it is not removed
   - treat forever?

Question 207

Identify prevention and control measures of staphylococcus aureus

1. General measures
2. Measures aimed at MRSA

Answer 207

1. General measures:
   •Antibiotic stewardship - decrease selection pressure •Remove or avoid unnecessary prosthetic material •Hand hygiene
2. Measures aimed at MRSA:
   •Contact precautions for MRSA – gown, gloves, hand hygiene •Pre-operative antibiotics
   •Active surveillance? With decolonization?
   •In ICUs – universal decolonization with chlorhexidine

Question 208

Identify bug

**mainly from hip replacement, FOLEY CATHETER

● Gr+ve  cocci in clusters
● Coagulase-negative 
● Virulence factors:  Glycocalyx: the exopolysaccharide “slime” helps in adhesion, antiphagocytic and makes it resistance to antibiotics 
● beta- lactamase 
● Mutant Penicillin-binding protein

Answer 208

STAPHYLOCOCCUS EPIDERMIDIS

**Foley catheter

Question 209

Identify bug

**cause UTI in sexually active young women

● Coagulase negative
● Virulence related to binding to epithelium
● Almost entirely associated with urinary tract infection.
● Symptoms:Infected women usually have dysuria (pain on urination) pyuria (pus in urine) and numerous organisms in urine

Answer 209

STAPHYLOCOCCUS SAPAROPHYTICUS

Question 210

1. What 2 tests can you use to diagnose staphylococcus

2. What test differentiate between staphylococcus and streptococcus

Answer 210

1. Coagulase and catalase test
2. Catalase test
   - helps diff staphylococcus (catalase +) from streptococcus (catalase -)
   * *Staph will produce bubbles while strep will not

Question 211

Summary of staph infections

Answer 211

1. Gram+ve clusters, divide in all directions, beta-hemolysis, coagulase, and extracellular enzymes, Abscess in the soft tissue and skin, cellulitis, endocarditis, food poisoning, furuncle, carbuncle, impetigo, osteomyelitis, pneumonia, scalded skin syndrome, septic arthritis, toxic shock syndrome, and wound infection
2. Preformed heat-stable enterotoxin, food poisoning occurs
   quickly. Same with TSST (super-antigen); PVL.
3. Formation of abscess in the breast or lung, empyema.
4. IV catheter sites, prosthetic implants (heart valves, vascular
   grafts) get infected.
5. Urinary tract infection
6. MSSA vs MRSA
7. Nosocomial infections, screening for HCWs

Question 212

Gram negative classification map

1. Identify 2 groups of gram negative (according to shape)
2. Further differentiation?

**Give examples of bacteria that ferment maltose vs one that doesn’t

3. Differentiate aerobic (in terms of nutrient requirement for growth)
4. STructures that lack what enzyme can be classified as lactose + or -
   - which is definitely pathogenic?

Answer 212

1. Rods and Cocci (in pairs)
2. A. Rods
   - Aerobic
   - Anaerobic (bacteroides)

B. Cocci (in pairs) - neisseria

• Maltose (+) ; ferment maltose to lactate e.g N. Menigitidis
• Maltose (-) ; N. Gonorrhoeae

3. Aerobic
   A. Fastidious growth requirements (blood component)
   - Intracellular growth (+); brucella, legionella, francisella, bordetella
   - Intracellular growth (-); Haemophilis (require factors X and V), campylobacter (seagull shape)

B. Simple growth requirements

• Oxidase (+); pseudomonas, vibrio (comma shape)
• Oxidase (-); lactose (+) or (-)

4. Oxidase (-) ; enterobacteriaceae
   A. Lactose (+); E.coli, klebsiella, enterobacter, serratia, citrobacter
   B. Lactose (-) DEFINITELY PATHOGENIC - Salmonella (H2S), shigella, proteus (swarming)

Question 213

1. What is the major component of a gram negative bacterial cell wall (e.g enterobacteriaceae)
2. Identify parts used in serological typing (3)
   - which is part of LPS
   - which is capsular
   - which is flagella
3. Do all enterobacteriaceae ferment glucose? Have oxidase? Ferment lactose?

Answer 213

1. Lipopolysaccharide (LPS)
   - All gram Negative rods have LPS in cell wall
2. Serological typing
   - O antigen (polysaccharide portion of LPS); highly variable per bacteria
   - K (capsular) antigen
   - H (flagella) antigen
3. • all ferment glucose
   • oxidase negative
   • lactose fermentation varies; salmonella, shigella and proteus do not ferment lactose

Question 214

1. What are the 2 products of lactose fermentation
2. Classify the enterobacteriaceae types according to;
   A. ferment lactose (3)
   B. does not ferment lactose (4)
   C. ferment lactose slowly (2)
3. LPS struture (3 parts)
   A. What is major component of LPS
   B. Polysaccharide on the outside?
   C. Main source of immunogenicity - endotoxin activity

Answer 214

1. Galactose + Glucose
2. Lactose fermentation
   A. ferment lactose; Klebsiella, E.coli, Enterobacter
   B. does not ferment lactose; Shigella, Salmonella, Yersinia, proteus. (Pseudomonas is oxidase positive)
   C. ferment lactose slowly; serratia, vibrio
3. LPS
   A. KDO - core
   B. O-antigen; outside
   C. Lipid A; endotoxin - immunogenicity

Question 215

Proteins made in the bacteria need to be transported out in an expensive and ATP dependent process - use of secretion systems

1. Identify the 5 types
2. Which is sec dependent
3. Which uses conjugation
4. Which is a pathogenicity island
5. Which is chaperone dependent

Answer 215

1. Type I, II, III, IV, V
2. Sec dependent - Type II and V
3. Conjugation - Type IV
   - F pilus
4. Pathogenicity Island - Type III
5. Chaperone - Type I

Question 216

1. Identify the virulence factors of E.coli (7)

• component of LPS
• have capsule?
• secretion system?
• resistance? (2)

2. E.coli can affect what organs ? (5)

Answer 216

1. E.coli is Gram Negative
2. Endotoxin (lipid A)
3. Capsule
4. Antigenic phase variation
5. Type III secretion system
6. sequestration of growth factor
7. Resistance to serum killing
8. Antimicrobial resistance
9. E.coli affect;
   - CNS
   - Lower respiratory tract
   - Bloodstream
   - GI tract
   - Urinary tract

Question 217

1. Identify various infections /diseases caused by E.coli (6)
2. Identify treatment and control of E.coli (4)

Answer 217

1. Infections/diseases (6)
   - Bacteremia
   - Gastroenteritis
   - Hemolytic-uremic syndrome
   - UTI
   - Neonatal meningitis
   - Septicemia
2. Treatment and control (PREVENT DEHYDRATION)
   - enteric pathogens treated SYMPTOMATICALLY unless disseminations occur
   - ANTIBIOTIC THERAPY guided by in vitro abx susceptibility tests
   - Infection control in hospital
   - HIGH HYGIENIC standards

Question 218

E.coli is not classified as intracellular or extracellualr becuase they can be indifferent locations.

• *The strains of E.coli that cause GASTROENTERITIS are divided into what 5 types
  1. non invasive
  2. starts to invade
  3. go inside cell
  4. start outside cell
  5. produce toxin

Answer 218

• TPIAH
  1. ETEC (Enterotoxigenic)
• non invasive, produce heat labile (LT) and heat stable (ST) enterotoxins, watery and traveler diarrhea

2. EPEC (Enteropathogenic)
   - moderately invasive, DESTROY MICROVILLI, underdeveloped
3. EIEC (Enteroinvasive)
   - OMP, entry site is in M CELLS**
4. EAggEC (Enteroaggregative)
   - non invasive
5. EHEC (Enterohemorrhageic)
   - moderately invasive, does not produce LT or ST, produce SLT - shiga like toxin aka verotoxin. O157:H7
   - bloody diarrhea

Question 219

Identify the gastroenteritis caused by E.coli

• Plasmid-mediated
• Noninvasive.
• Fimbrial adhesins, CFA I and CFA II.
• Produce heat labile (LT) and heat stable (ST) enterotoxins.
• Watery diarrhea in infants and TRAVELER’S diarrhea.
• NO INFLAMMATION and NO FEVER.

Answer 219

Enterotoxigenic E.coli (ETEC)

• Non invasive
• produces heat-labile and heat-stable enterotoxins
• No inflammation or invasion
• T - Traveler’s (watery diarrhea)

Question 220

Identify the E.coli strain in gastroenteritis

• Non fimbrial adhesion (intimin).
• Moderately invasive.
• Does not produce LT or ST. NO TOXINS PRODUCED
• Attachment-Effacement (eae).
• Bundle forming pilus (Bfp).
• DESTRUCTION of MICROVILLI (adhere to apical surface).
• INFANTILE/PEDIATRIC DIARRHEA, similar to ETEC, some inflammation, no fever.
• Common in underdeveloped countries

Answer 220

Enteropathogenic E. Coli (EPEC)

• No toxin produced
• Adheres to apical surface, flattens villi and prevents absorption
• P - Pediatric diarrhea

Question 221

Identify E.coli strain in Gastroenteritis

• Nonfimbrial adhesions, possibly OMP.
• Invasive (penetrate and multiply within epithelial cells).
• Entry site is the M cells
• Does not produce shiga toxin.
• Dysentery-like diarrhea (mucous, blood), severe inflammation, fever.
• Very large plasmid (pINV).

Answer 221

Enteroinvasive E.coli (EIEC)-like shigella

• Microbe invades intestinal mucosal (VIA M CELLS) and causes necrosis and inflammation
• I - Invasive; dysentery. Clinical manifestations similar to shigella

Question 222

Identify E.coli strain in gastroenteritis

• Adhesins not characterized (GVVPQ fimbriae).
• Noninvasive.
• Produce ST-like toxin and a hemolysin.
• Persistent diarrhea in young children without immunization, NO FEVER.

Answer 222

Enteroaggregative E. coli (EAggEC)

**Noninvasive

Question 223

Identify E.coli strain in gastroenteritis

• Similar to EPEC, moderately invasive.
• Does not produce LT or ST, but SHIGA-LIKE TOXIN (SLT) (encoded on a phage), also called verotoxin, cytotoxic to intestinal villi and colon epithelial cells (lysogenic conversion)
• Pediatric diarrhea, copious BLOODY DISCHARGE hemorrhagic colitis), intense inflammation and hemolytic uremia.
• O157:H7 (most common strain in USA)
**In spinach

Answer 223

Enterohemorrhagic E. coli (EHEC)

• Does not ferment sorbitol
• Triad: Hemorrhagic, Hamburgers (spinach), Hemolytic-uremic syndrome

Question 224

What are common causes of UTI in;

1. Community acquired UTI (3)
2. Hospital (nosocomial) acquired UTI (3)

• gram neg cause which? E.g
• gram positive cause which? E.g
• E.coli?
• candida?

Answer 224

1. Community acquired
   A. E.coli
   B. Coagulase-negative staphylococci
   C. Other Gram-positive; Staphylococcus epidermidis (sexually active young females), staphylococcus aureus, enterococcus faecalis
2. Hospital (nosocomial) - from Foley catheter
   A. Candida
   B. Proteus mirabilis
   C. Other gram negatives; klebsiella, enterobacter, serratia, pseudomonas aeruginosa

Question 225

***High yield

The following is a virulence factor for which bacteria type?

P fimbria - pyelonephritis-associated pili (PAP
pili) which binds specifically to the P blood group
antigen that contains a D-galactose-D-galactose residue.

Answer 225

Virulence factors of UROPATHOGENIC E. COLI

• E.coli that causes UTI is called uropathogenic E.coli
• Woman with frequent UTI has a P blood group antigen

Question 226

1. Identify the bacteria species that DO NOT FERMENT LACTOSE but ferment glucose by producing H2S (TSI)
   - This species is common in the GI tract of ANIMALS, but not in human flora

A. What are the 2 species of the genus
b. Subspecies

Answer 226

SALMONELLA spp
**lactose (-), oxidase (-), aerobic that need SIMPLE growth requirement, gram negative rods

A. Genus only 2 species ; S. Bongori and S. Enterica
B. S. Enterica; 6 subspecies. Enterica has more than 2500 serotypes
C. S. Enterica serotypes choleraesuis - swine and human pathogen

• *Antigens - O, H and capsular Vi
• *Facultative intracellular growth

Question 227

Identify diseases caused by salmonella spp. (4)

• one is the most common cause of food-borne infections - hard to develop immunity
• S. Typhi
• infect blood

Answer 227

1. Gastroenteritis; most common cause of food-borne infections - indicates it’s hard to develop immunity
2. Typhoid (enteric) fever - strain is S. Typhi
3. Bacteremia
4. Localized infections in other sites (osteomyelitis, meningitis)

Question 228

Identify condition

• 6-30 days of incubation, initial symptoms include FEVER,
HEADACHE, malaise, and anorexia. Some have SKIN
RASH with rose-colored spots.
• Starts in the small intestine through Peyer’s patches,
and then spread to the phagocytes of liver, gallbladder,
and spleen-bacterimia.
• Survival in the phagosomes in phagocytic cells-carrier
state.

Answer 228

Typhoid (Enteric) Fever

• Salmonella enterica serotype Typhi, aka S. typhi
• S. typhi and S. paratyphi, etiological agents
• Typhoid fever is transmitted only by humans.

Question 229

Identify condition

• Caused by Non-typhoid Salmonella
• Invasion of epithelia and subepithelial tissue of the small and large intestines.
• PMN response limits the infection to the gut and the adjacent mesenteric lymph node.
• Infective dose very high (100,000 CFU).
• Gastric acid important host defense.

Answer 229

ENTEROCOLITIS

Question 230

Identify condition

• Only about 5-10% of Salmonella infections.
• Underlying chronic disease: sickle cell anemia or cancer (USMLE).

Answer 230

SEPTICEMIA (same as bacteremia)

• Bacteremia results in seeding of many organs, with osteomyelitis, pneumonia, and meningitis as the most common sequelae.

Question 231

1. How does salmonella spread and multiply
   - which route is in all serotypes
   - which multiply in lamina propria with uncertain mechanisms
   - spread within macrophages
   - no symptoms
2. Identify treatment and prevention of salmonella
   - is there a vaccine? How effective?

Answer 231

1. Spread and multiply
   - FECAL ORAL route (all serotypes)
   - The DIARRHEA-CAUSING SALMONELLA multiply in the lamina propria with uncertain mechanisms
   - ASYMPTOMATIC carriers (S. Typhi)
   - Typhoid bacilli are not killed and they steadily multiply within MACROPHAGES
2. Treatment/prevention
   - symptom relief
   - unrestricted use of antibiotics; selection for resistant bacteria
   - Poultry industry
   - vaccine against S. Typhi (50-70% effective and short term protection
   - education

Question 232

Identify bacteria species

• four species (including dysentery)
• all 4 species are pathogenic in humans and cause similar disease
• this species is the most effective among ENTERIC PATHOGENS
• *Identify 4 species
• which is in developing countries
• which cause mildest disease and it is 75% of infections in USA

Answer 232

SHIGELLA spp.
**Lactose (-), oxidase (-), aerobic with SIMPLE growth requirement, gram negative rods

4 species
● S. dysenteriae (group A); in developing countries
● S. flexneri (group B).
● S. boydii (group C).
● S. sonnei (group D); causes mildest disease and accounts for 75% of all shigella infections in the US

Question 233

Characteristics of shigella spp

1. Similar to what other bacteria?
2. Lactose? Gram status? Shape?
3. Do they produce H2S?
4. Motile?
5. Ferment glucose? Produce gas? ‘
6. Toxin?
7. Animal reservoir?

Answer 233

1. SHIGELLA is very similar to invasive E. coli.
2. Non-lactose fermenting, gram-negative rods.
3. They do not produce H
4. Nonmotile.
5. Produce no gas when fermenting glucose.
6. Shiga toxin (Shigella dysenteriae)
7. No animal reservoir

**Shigella is intracellular (can only grow inside cells)

Question 234

Identify virulence mechanism of shigella toxin

• what is the target
• is bacteremia common?

Answer 234

SHIGELLA TOXIN
- AB toxin; B is a binding site, A cleaves 28S rRNA

• Target: M cells in Peyer’s patches.
• Bacterimia is uncommon with Shigella.
• S. dysenteriae strains produce an exotoxin, Shiga toxin, similar to the toxin made by EHEC. AB5, A cleaves the 28S rRNA in the
60S ribosomal subunit.

Question 235

What 2 gram negative bacteria are invasive and participate in mucosal immunity (Peyer’s patches/ MALT)

**What cell and immunoglobulin are involved in mucosal immunity

Answer 235

Shigella and E.Coli are Invasive

• Mucosal immunity; Recognized by T cells (clonal expansion) - B cells (IgA) - exocytosis secrete IgA on the luminal side
• High IgA - resistant to bacterial infections

**remember gamma delta T cell and IgA are involved in mucosal immunity

Question 236

Identify condition ***High yield

• Arthritis, conjunctivitis and urethritis appear after the intestinal infections by one of the intestinal pathogens such as Shigella, Yersinia enterocolitica, Salmonella, Klebsiella pneumoniae, and Campylobacter.
• Cause is unclear, may be due to an autoimmune response.
• Most patients are male (HLA-B27-positive).

Answer 236

REITER’S SYNDROME

Question 237

1. How do you make a clinical diagnosis of shigella (when patient has dysentery)
2. What is the clinical manifestation of shigella?

Answer 237

1. Presence of PMN (polymorphonuclear neutrophils)
   - Methylene blue stain of a fecal sample to determine the presence of PMN. If present, they could be an invasive organism such as Shigella, Salmonella, or Campylobacter.
2. Clinical manifestations
   - tenesmus, watery, bloody diarrhea
   - incubation 1-4 days. Symptom begins with fever and abdominal cramps followed by diarrhea (watery first and then later contains blood and mucus)

Question 238

1. Identify transmission of Shigella
   - 4 Fs
2. Identify treatment and prevention of shigella

Answer 238

1. Transmission
   • Only to HUMAN.
   • Fecal-oral route: (4 F’s) fingers, flies, food, and feces.
   • Food-borne outbreaks outnumber waterborne by 2 to 1
   • 50% shigella positive samples come from children younger than 10 years of age.
   • No carrier state.
2. Treatment and prevention
   • Fluid and electrolyte replacement. In severe cases, a fluoroquinolone, eg. Ciprofloxacin, is the choice.
   • Remember need to check the multiple drug resistance (plasmid borne).
   • Emphasis on the personal hygiene.

Question 239

Identify 2 other enterobacteriaceae apart from shigella and salmonella

1. produce prominent capsule for enhanced virulence; can cause community-acquired or hospital acquired lobar pneumonia
2. • can cause UTI
   • this bacterium produces large quantities of urease, which split urea into CO2 and ammonia
   • this process raises urine pH, precipitating magnesium and calcium which cause kidney stones

Answer 239

1. Klebsiella pneumoniae
   - produce prominent capsule for enhanced virulence; can cause community-acquired or hospital acquired lobar pneumonia
2. Proteus mirabilis
   - can cause UTI
   - this bacterium produces large quantities of urease, which split urea into CO2 and ammonia
   - this process raises urine pH, precipitating magnesium and calcium which cause kidney stones

Question 240

Summary of enteric bacteria infections

1. gram status? Component of cell wall? Antigens (3)? Fermentation? Oxidase?
2. What cause disease? Transport systems? Resistance?
3. what causes gastroenteritis? Other infections
4. Other diseases
5. What does shigella cause?
6. Klebsiella?

Answer 240

1. Gram-negative cell walls, lipopolysaccharide, O-K-H antigens, lactose and glucose fermentation, oxidase negative.
2. Virulence factors, type III secretion system, antibiotic
   resistance, and serum resistance.
3. Gastroenteritis caused by E. coli strains, UTI (community
   and hospital-acquired), Septicemia, Lung and CNS
   infections
4. Salmonella enterocolitis, professional pathogen, typhoid
   fever, Payer’s patches, food poisoning, septicemia (sickle
   cell anemia or cancer)
5. Shigella, pediatric dysentery, intracellular, Reiter’s
   syndrome
6. Klebssiella pneumonia, capsule, Proteus mirabilis, kidney
   stones

Question 241

1. ***What is the hallmark of BORDETELLA PERTUSSIS infection

• gram status?
• need oxygen? Oxidase? Catalase? Ferment glucose?
• nutrition requirement?
• clinical symptom

Answer 241

1. LYMPHOCYTOSIS - bordetella pertusis

• gram negative coccobacillus, small and encapsulated
• DOES NOT FERMENT GLUCOSE
• Nutritionally FASTIDIOUS, enriched media; bordet-gengou medium or charcoal containing medium with horse blood (regan Lowe)
• clinical symptom; recurrent/violent cough (whooping) last up to 6 weeks. Capable of invading respiratory tract and cause PERTUSIS OR WHOOPING COUGH

Question 242

Identify bordetella pertusis virulence factors

1. • Filamentous hemagglutinin (FHA) .
   • Pertussis toxin (6 subunits: S1-S3, 2-S4, S5).
   • Pili and pertactin
2. • Pertussis toxin.
   • Invasive adenylate cyclase
   • Dermonecrotic toxin (lethal toxin).
   • Tracheal cytotoxin-Peptidoglycan fragments.
   • LPS-Lipid A and lipid X (Cause inflammatory responses)

**what parts do BP often colonize? Why?

Answer 242

1. Adhesins
2. Toxins
   - Overactivates adenylate cyclase (increase cAMP) by disabling Gi; impairing phagocytosis to permit survival of microbe

*****BP colonize airway (respiratory tract) mostly because it NEEDS OXYGEN TO GROW

Question 243

1. How do you diagnose Pertussis diagnosis?
   - advantages?
   - Disadvantages?
2. Prevention and immunization
   - pertussis vaccine is give with?
   - how many doses before school entry?
3. Treatment
   A. B.pertussis is susceptible to what drugs in vitro?
   B. Administration of what during the catarrhal stage of disease promotes elimination of organisms and may have prophylactic value

Answer 243

1. Pertussis diagnosis
   - DFA test; Direct fluorescent antibody
   - Advantages; FAST
   - Disadvantages; May not be specific
   * * The antibody is not as specific as GAS (Group A strep)
   - PCR (polymerase chain reaction)
2. Prevention with immunization
   - Pertussis vaccine is usually administered in combination with DTap (toxoids of diphtheria and tetanus)
   - 5 doses of pertussis vaccine recommended before school entry; 2, 4, 6 and 15-18 months of age and a booster dose at 4-6 years old.
3. A. B.P is susceptible to SEVERAL ANTIMICROBIAL drugs
   B. ERYTHROMYCIN
   C. Treatment after onset of paroxysmal phase rarely alters the clinical course. Oxygen inhalation and sedation may prevent ANOXIC DAMAGE to the brain

Question 244

Identify bacteria

• OPPURTUNISTIC (only when immune system is immunocompromised)
• Gram negative rods
• Aerobic with simple growth requirements
• Oxidase (+)
• UBIQUITOUS; soil, river and hospitals

**green pigment? Blue pigment? Dark red pigment? Black pigment?

Answer 244

PSEUDOMONAS AERUGINOSA

• Gram negative rod; most strains are hemolytic
• Non-fermenter
• Motile with flagella
• Aerobic
• Oxidase positive
• Simple growth requirement.
• Ubiquitous, soil, river, and hospitals, etc.

•*** Green fluorescent pigment PYOVERDIN; nonfluorescent bluish pigment PYOCYANIN; dark red pigment PYORUBIN; black pigment
PYOMELANIN.

Question 245

Identify pseudomonas pigments and functions

1. Siderophore that binds iron for use in metabolism
2. Catalyze production of superoxide and hydrogen peroxide. Also stimulate IL-8 release for neutrophil recruitment
3. 2 functions unknown

Answer 245

1. FLUORESCENT pigment PYOVERDIN: a siderophore that binds iron for use in metabolism.
2. BLUISH pigment PYOCYANIN: catalyzes the production of
   superoxide and hydrogen peroxide. Also stimulates IL-8
   release for neutrophil recruitment.
3. DARK red pigment PYORUBIN; BLACK pigment PYOMELANIN.
   Functions unknown.

Question 246

1. Does pseudomonas ferment lactose? Have flagella?
2. What is the main respiratory problem caused by pseudomonas aeruginosa - from FRUSTRATED PHAGOCYTOSIS
3. What component of the pseudomonas help PREVENT PHAGOCYTOSIS? How?
4. What exotoxin component makes it resistant to antibiotics - they are UBIQUITOUS

Answer 246

1. Pseudomonas aeruginosa DO NOT FERMENT lactose. They HAVE FLAGELLA that help them swim
2. CYSTIC FIBROSIS (CF); Problem with iron transport so pseudomonas can colonize it
   • Neutrophils in their sputum trying to engulf bacteria but it is too big to eat - FRUSTRATED PHAGOCYTOSIS; neutrophil burst, pus forms and lungs would be damaged.
3. MUCOIDY of P.aeruginosa; they produce all these polysaccharide to help PREVENT PHAGOCYTOSIS
4. Bacterial BIOFILMS
   - exopolysaccharide matrix enclosed bacterial COMMUNITY, different from bacteria in suspension
   - 100-1000 fold more resistant to antibiotics
   - one of the CAUSES FOR CHRONIC INFECTIONS
   - BIOFILMS are UBIQUITOUS

Question 247

Identify virulence factors of pseudomonas aeruginosa

1. similar mode of action as diphtheria toxin- ADP-ribosylation of EFII. Controlled by transcriptional activator subject to iron regulation.
2. may be a required for dissemination from burn wounds and for
   tissue destruction in chronic lung infections. In vitro, it ADP-ribosylates several proteins (vimentin, ras). Type III secretion system.
3. breaks down elastin, collagen, immunoglobulins, complement
   components.
4. hydrolysis of phospholipids leading to tissue damage
5. PROTEOLYSIS leading to tissue damage
6. Promotes adherence to respiratory epithelium, interferes with
   effective phagocytosis and may be immunostimulatory.

Answer 247

1. Exotoxin A; inactivate EF-2 (elongation factor)
2. Exoenzymes S
3. Elastase
   - Elastase production is controlled by a transcriptional activator, LasR, which senses the presence of other P. aeruginosa cells in a process called “quorum sensing”. Iron-regulated.
4. Phospholipase C and Heat stable phospholipase
5. Alkaline phosphorescent
6. Alginate; polysaccharide with capsule in pseudomonas. Right now you get alginate from seaweed

Question 248

1. Identify 3 most common infections caused by Pseudomonas

2. Identify predisposing factors (local, systemic, local and systemic) according to the various types of infections 
A. Pneumonia 
B. Osteomyelitis 
C. Septicemia 
D. Meningitis/Endocarditis/UTI 
E. Panophthalmitis 
F. Malignant otitis externa

Answer 248

1. Most common
   - Burned patients
   - Neutropenic patients
   - Patients with CF
2. A. Pneumonia
   - local; CF, surgery, tracheostomy

B. Osteomyelitis
- local; IV drug use, diabetic, trauma

C. Septicemia

• systemic; neutropenia, neonates
• local and systemic; burns

D. Meningitis/Endocarditis/UTI
- Local; neurosurgery, IV drug use, kidney stones, catheterization

E. Panophthalmitis
- local; corneal injury (contacts)

F. Malignant otitis externa
- Systemic; diabetes

Question 249

1. Identify the condition
   - infection of hair follicles
   - Pseudomonas grow perfectly in hot tub
   - If you just shaved your hair on legs (wax) and you immediately go into the hut tub, you will have folliculitis the next day
2. From P.aeruginosa bacteremia in neutropenic patients
3. How do you get contact lenses infected with p. Aeruginosa?

Answer 249

1. PSEUDOMONAS FOLLICULITIS
   - result from immersion in contaminated water, such as hot tubs, whirlpools and swimming pools
   - A secondary infection in people who have ACNE or who depilate their legs
   - FINGERNAIL INFECTION
2. ECTHYMA GANGRENOSA
3. Must be in IMMUNOCOMPROMISED CONDITION before pseudomonas can come in
   - pseudomonas grow on the agar with HEMOLYSINS
   - pseudomonas is also capable of producing a wide variety of other exotoxins; contribute to local inflammation, tissue destruction and pus formation

Question 250

1. How do you treat pseudomonas aeruginosa?

Combination? Why?
**what is a major issue in management of nosocomial (hospital acquired) infection. How?

Answer 250

1. COMBINATION THERAPY; because P.aeruginosa is RESISTANT to many antibiotics
   - tailor treatment to sensitivity
   - resistant strain can emerge during therapy

**Combination of; Anti-Pseudomonas penicillin, ticarcillin or piperacillin + aminoglycoside (tobramycin)

• *MULTIDRUG RESISTANCE - major issue; due to acquisition of; chromosomal beta lactamase, extended spectrum beta lactamase (ESBL), porin channel mutations and efflux pumps
• • Antibiotics has to come in and cannot come in if there is some mutation in porin channel

Question 251

Identify bacteria

• COLISTIN ANTIBIOTIC RESISTANT
• aerobic, gram negative bacteria that is widely distributed in soil and water and can occasionally be cultured from skin, mucous membranes, secretions and hospital environment
• often are commensalism but occasionally cause nosocomial infection
• A baumannii has been isolated from blood, sputum, skin, pleural fluid and urine usually in device-associated infections

**are they multidrug resistance?

Answer 251

ACINETOBACTER

**Acinetobacter strains are often MULTIDRUG RESISTANT and therapy of infection can be difficult. In many cases the only active agent may be colistin

Question 252

**WHAT ARE ESKAPE PATHOGENS (6)

Acronym that stands for what?

**Identify CDC threat level urgent vs serious

Answer 252

ESKAPE is an acronym standing for bacterial pathogens commonly associated with antimicrobial resistance

Enterococcus faecium 
Staphylococcus aureus 
Klebsiella pneumonia 
Acinetobacter baumannii 
Pseudomonas aeruginosa 
Enterobacter species 

• CDC threat level URGENT; Carbapenem-resistant Enterobacteriaceae (CRE); Clostridium difficile; Drug-resistant Neisseria gonorrhoeae
• CDC threat level SERIOUS; VRE; MRSA; Multi-drug resistant Acinetobacter infections; Multidrug resistant Pseudomonas infections

Question 253

Identify the different types of pneumonia

1. pneumonia that occurs 48 hours or more AFTER ADMISSION and did not appear to be incubating at the time of admission.
2. type of pneumonia that develops ≥48 hours after endotracheal intubation.

**why was category made?

Answer 253

1. HAP (or nosocomial pneumonia)
2. VAP (ventilator associated pneumonia)
   - from staphylococcus aureus

**This category was used to identify patients at risk for infection with MDR (multidrug resistant) pathogens

Question 254

What bacteria types can be found on a MacConkey agar
*why form pink colonies?

**what bacteria types can’t grown

Answer 254

Fermentation of lactose - pink colonies

• MacConkey agar is an indicator, a selective and differential culture medium for bacteria designed to selectively isolate GRAM-NEGATIVE and ENTERIC (normally found in intestinal tract) bacilli and differentiate them based on lactose fermentation
  E,g of what grows; E.coli, citrobacter, klebsiella, Enterobacter, Serratia (weak fermenter)

**Gram positive CANNOT GROW; agar contains bile salts that inhibit gram (+) and also crystal violet dye, neutral red dye (turns pink if microbes are fermenting lactose)

Question 255

Summary of bordetella and pseudomonas infections

Answer 255

• Gram-ve coccobacilli, nutritionally fastidious, special growth medium, whopping cough, strictly aerobic, another strict aeroic mycobacterium, lymphocytosis

• Intracellular growth, adenylate cyclase, cAMP, deregulation
of ion channel, diagnosis, direct fluorescent antibody, DTaP
vaccine, whole cell vs acellular vaccine, erythromycin
treatment

• Pseudomonas G-ve rod, oxidase positive, simple growth
requirement, pigments, antibiotic resistance mechanisms

• Opportunistic infections, burns, cystic fibrosis, biofilms,
airway microbiota,Pseudomonas folliculitis, Ecthyma
gangrenosa, and MDR

• Acinetobacter, ESKAPE, Antimicrobial resistance (MDR vs
XDR), HAP, VAP, Infection surveillance,

Question 256

Simplifying microbiology

Identify 3 gram positive

Answer 256

Gram positive (3)

1. Staphylococcus (coNS, aureus, MRSA)
2. Streptococcus (pyogenes, pneumonia, PCN-resistant)
3. Enterococcus (faecalis, faecium, VRE)

*some antibiotics can cover all 3 gram positive (MRSA, PCN, VRE)

Question 257

Simplifying microbiology

Identify gram negative (3 categories)

Answer 257

1. Weak/Piddly (7)
   - Haemophilus, Morexella, Morganella, Shigella, Salmonella, Providencia, neisseria
2. Fence Bugs (3) - PEK - some are easy, some are resistant
   - Proteus
   - Eschericia coli
   - Klebsiella
3. SPACE (5); toughest - need 2 abx because they are resistant
   - Serratia
   - Pseudomonas
   - Acinetobacter
   - Citrobacter
   - Enterobacter

Question 258

Simplifying microbiology

1. Identify atypicals (3)
2. Identify anaerobes (3); mouth to colon

Answer 258

1. Atypicals; no cell wall so it doesn’t light up in testing
   A. Chlamydia
   B. Mycoplasma
   C. Legionella
2. Anaerobes (mouth - SI - LI)
   A. Peptostreptococcus
   B. Bacteroides
   C. Clostridium

Question 259

Differentiate the following agents

1. • Ideal scenario for killing bacteria
   • lethal to susceptible microorganisms
   • give 2 examples?
2. • works but may have limitations
   • inhibit growth of susceptible microorganisms
     Give example

Answer 259

1. Bactericidal Agent
   - penicillins, cephalosporins
2. Bacteriostatic Agent
   - sulfonamides

Question 260

Identify spectrum of activity of antibiotics (2)
*Give examples

Which do these belong?

• nafcillin
• imipenem
• piperacillin
• for gram negative and gram positive

Answer 260

1. NARROW; effective against a small number of microorganisms
   - Pen G; Gram positive organisms (strep)
   - Nafcillin; Staph and strep
2. BROAD; effective against a large number of microorganisms. *(has more side effects and resistance)
   - Piperacillin/Tazobactam
   - Imipenem; Gram positive, gram negative and anaerobic organisms

Question 261

Identify the following terms;

1. Concentration of drug required to inhibit or kill a microorganism cannot be achieved safely.
   - what is another type where some abx can’t penetrate
2. Enhancement of action of one drug by another (1+1 =4)
   - give examples (which inhibit folic acid synthesis), which is used in enterococcus and pseudomonas
3. Decreased action of one drug by another
   - give example

Answer 261

1. RESISTANT Microorganism
   - Intrinsic resistance
2. SYNERGY
   - Trimethoprim/sulfamethoxazole; sequential inhibition of folic acid synthesis
   - Penicillin/aminoglycoside; In enterococcus (increased penetration of aminoglycoside as penicillin breaks down cell wall) and pseudomonas (different site for mechanism of action becuase it is a space resistant drug)
3. ANTAGONISM (rare) ; bacteriostatic/bactericidal
   - more in vitro than vivo
   - static agents can inhibit “active” processes of cidal agents
   - Most cidal agents require ACTIVE cell division or ACTIVE protein synthesis for expression of their bactericidal activity

Question 262

Identify effects

• persistent effect of an antimicrobial on bacterial growth following brief exposure of organisms to adrug
• AMINOGLYCOSIDES and FLUOROQUINOLONES have a high degree of this effect
• *above MIC (minimum inhibitory concentration) is GOOD
• *Below MIC is BAD - lead to RESISTANCE (low level of abx taht will not kill the bacteria but make it resistant)

Answer 262

POSTANTIBIOTIC EFFECT (PAE)

Question 263

Identify the 2 aspects of pharmacodynamics

1. • killing DEPENDENT on PEAK CONCENTRATION (you kill more bugs, the higher the peal conc 10x MIC)
   • optimal kill occurs when conc exceeds 10x MIC
   • give examples (2)
2. • Killing is dependent on amount of time the concentration stays above the MIC (40-50%)
   • give example

Answer 263

1. Concentration Dependent Killing
   - QUINOLONES, aminoglycosides (postantibiotic effect)
   * *disadvantage is that you increase adverse effects (you are increasing peak but don’t really kill the bug)
2. Time Dependent Killing
   - Beta lactamase antibiotics (penicillins, cephalosporins)

Question 264

These are the mechanism of action of what agents?

• Inhibit cell wall synthesis
• Inhibit protein synthesis or structure
• Interfere with cell membrane function
• Interfere with DNA/RNA synthesis
• Inhibit metabolism

Answer 264

MoA of ANTIMICROBIAL AGENTS

Question 265

Identity antimicrobial agent examples based on the MoA

• *Inhibitors of cell wall synthesis (4 types)
  1. Prevents cross-linking of peptidoglycan strands by INHIBITING TRANSPEPTIDASES
  2. Inhibits peptidoglycan syntheses and polymerization of linear peptide
• *Identify 2 other examples

***what is the MAIN EFFECT OF beta-lactams (give 4 examples)

Answer 265

1. Penicillins/Cephalosporins/Carbapenems/Aztreonam (beta-lactams; breakdown peptidoglycan)
2. Vancomycin
3. Bacitracin
4. Cycloserine

***Beta - lactams (#1); DECREASE MORTALITY - penicillin/cephalosporins/carbapenems/aztreonam

**All INHIBIT CELL WALL SYNTHESIS

Question 266

Identity antimicrobial agent examples based on the MoA

• *Inhibitors of Protein Synthesis/Structure
  1.
• inhibit 30 S ribosome
• causes misreading of mRNA

2. Inhibits peptidyl transferase and peptide band formation
3. Inhibits 50 S ribosome (3)
4. • Inhibits binding of aminoacyl tRNA to ribosome
   • 30 S ribosome
5. 23 S ribosome

Answer 266

1. Aminoglycosides
2. Chloramphenicol
3. Erythromycin, clindamycin, lincomycin
4. Tetracyclines
5. Streptogramins/Linezolid

**ALL INHIBIT PROTEIN SYNTHESIS/STRUCTURE

Question 267

Identity antimicrobial agent examples based on the MoA

• *Interference with cell membrane function
  1. Cationic detergent (2)
  2. Fungal section (2)

Answer 267

1. Cationic detergent
   - Polymixin B
   - Colistin (used especially in trauma)
2. Fungal section
   - Azole
   - Polyene antifungals

**ALL INTERFERE WITH CELL MEMBRANE FUNCTION

Question 268

Identity antimicrobial agent examples based on the MoA

• *Interference with DNA/RNA synthesis
  1. Inhibits DNA-dependent RNA polymerase

2. Interferes with supercoiling of DNA by action on DNA hyraxes (topoisomerase II)

Answer 268

1. Rifampin
2. FLUOROQUINOLONES

**ALL INTERFERE WITH DNA/RNA SYNTHESIS

Question 269

Identity antimicrobial agent examples based on the MoA

• *inhibitors of metabolism
  1. Inhibits lipid synthesis (2)

2. Prevent synthesis of FOLIC ACID (2)

Answer 269

1. Isoniazid (TB), ethambutol
   - inhibit lipid synthesis
2. Sulfonamides, trimethoprim
   - sulfa inhibit folic acid synthesis

Question 270

Antimicrobial stewardship is term used to describe the prevention of overprescribing antibiotics (they can cause c-diff - pseudomembranous colitis).

What 3 main things are needed to confirm presence of infection

1. Distinguish between infections and other diseases
2. Physical findings, leukocytosis, pain, blood
3. Disrupt natural barriers, immunosuppressant, age

Answer 270

Confirm presence of infection

1. FEVER (tells you there is an infection)
2. Signs and symptoms
   - physical findings (crackles, SOB, erythema - redness to skin or soft tissue, dysuria)
   - leukocytosis/left shift (high WBC)
   - pain
   - blood
3. Predisposing factors
   - disrupt natural barriers (skin is a natural barrier)
   - Immunosuppressive state (HIV, elderly, active chemo, transplant)
   - Age

Question 271

Identify basic steps in antibiotic therapy (5)

Answer 271

1. Determine site of infection
2. Determine the causative organism(s) ; to determine which antimicrobial agents are effective against it
3. Select a drug based on; sensitivity of microbes, physiochemical properties, drug toxicity, patient xters
4. Follow patient for clinical response
5. Alter therapy as necessary

Question 272

Empiric Abx coverage

1. Identify infection sites that are difficult to culture (4)
2. What is recommended to do for empiric therapy to determine the causative organisms
3. What is very informative for selection of empiric antibiotic

Answer 272

1. Hard to culture; cellulitis, pneumonia, brain abcess, middle ear infections
2. CULTURE SITE before starting abx
3. Gram stains - very informative for selection of empiric abx

Question 273

Identify pharmacologically considerations for abx therapy (5)

Answer 273

1. Route of administration
2. Distribution
3. Routes of elimination
4. Drug interactions
5. Allergies

Question 274

Identify the following routes of administration

1. Mild to moderate infections
2. • moderate to severe infections
   • patient unable to take oral agents
   • when do you switch to oral?
3. Short term solution
   - when do you use this?

Answer 274

1. Oral candidates
2. IV candidates
   - if afebrile for 2-3 days, consider change to oral
3. IM
   - when IV access is not obtainable
   - also use it for long lasting penicillin in rare cases

Question 275

The following affects what pharmacologically considerations

• Bioavailability (100% bioavailability oral = IV)
• drugs or food interactions

Answer 275

Absorption

• drugs not orally absorbed e.g penicillin (acid stable vs acid labile), vancomycin
• erythromycin/ampicillin (stomach upset if you don’t take with food but decreased absorption if you take with food)

Question 276

The following affects what pharmacologically considerations

• Urine concentration
• Bone penetration
• lung tissue penetration
• Skin and soft tissue concentration
• meningitis (what drugs do you use? Why?)

Answer 276

Distribution

A. Meningitis;

• penetration into CNS when meninges are inflamed vs uninflammed
• Ceftriaxone vs Unasyn; lipophilic pass BBB so may need higher dose to make sure it penetrates into the CSF

Question 277

What 2 main factors affect route of elimination

• 2 means of drug clearance (organs)
• infection - what excretion is desired?

Answer 277

1. Renal vs Hepatic clearance
   - Reduce dose if you have renal insufficiency
   - recommendation for dialysis patients
   - Many drugs are eliminated through the renal system
2. UTI (Urinary Tract Infection)
   - Renal excretion is desired
   - High concentration of drugs are eliminated unchanged

Question 278

Identify drug interactions

1. Concurrent medication interferes with antibiotic
   - what abx do antacids interfere with
2. Antibiotic interferes with concurrent agent
   - what abx does warfarin interfere with?
   - what abx does theophylline interfere with?
   - what causes SEROTONIN STORM? How?

Answer 278

1. Antacid with QUINOLONES and TETRACYCLINE
2. • Bactrim/Erythromycin with Warfarin
   • Ciprofloxacin with Theophylline
   • Linezolid with SSRI inhibitor so increased serotonin

Question 279

What ways do microbials become resistant (3)

Answer 279

1. Certain organisms inherit resistance patterns from environmental exposure to abx
2. Resistance may be natural or may result from mutation, adaptation or gene transfer
3. Multiple resistance - plasmids

Question 280

Identify 5 mechanisms of resistance

Answer 280

1. Increased drug inactivating enzyme activity (beta-lactamases); penicillin/cephalosporins
2. Alter cell wall/membrane permeability
   - alteration of porin channel
3. Altered binding site/receptor of drug
   - macrolides
4. Drug efflux
   - FLUOROQUINOLONES
5. Increase endogenous metabolite
   - sulfonamides; bacteria may synthesize PABA to antagonize drug

Question 281

What are advantages and disadvantages of combination therapy

Answer 281

1. Advantages
   - treatment of mixed bacterial infections
   - treatment of several infections when the organism is unknown
   - enhance antibacterial activity; SYNERGY - endocarditis tx; pseudomonas spp.
2. Disadvantage
   - added risk of toxicity

Question 282

Identify the follwoing side effects

1. • All antibiotics, unless major significance may not be mentioned under each class of antimicrobial
   • skin, hematologic
2. Dose related toxicities
   - what is adverse effect of IMIPENEM? Amphotericin? Cefazolin?
3. Idiosyncratic reaction
   - what abx causes aplastic anemia? Great abx used in underdeveloped countries
4. What is superinfection? What are 2 examples**

Answer 282

1. Allergic reaction
2. • Imipenem; SEIZURES
   • Amphotericin; nephrotoxicity
   • Cefazolin; Neutropenia (dose and duration)
3. Aplastic anemia - Chloramphenicol
4. Superinfection; alteration of normal flora
   - Yeast infection
   - C-diff

Question 283

Identify ways in which therapy fails (1)

2. Meningitis and pneumonia results from? What is unique about aminoglycosides and lungs?
3. What is the treatment for abcess
4. Identify 2 superinfections

Answer 283

1. Delays in beginning therapy; start as soon as you get culture results
2. Inadequate drug or drug levels;
   - pt not cultured before therapy
   - Meningitis; inadequate penetration of drug into CNS
   - Pneumonia; Aminoglycosides - don’t penetrate lungs well so need higher dose. Balance high enough peak with low enough trough
3. Host defenses inadequate
   - immunocompromised host; cancer, HIV
   - success depends on achieving level of antibacterial activity
4. Abcess; incision and drainage before abx
5. Superinfection; C-DIFF and yeast
6. Microbial resistance ; developed during therapy or intrinsic resistance
7. Drug interactions; binding, compliance
8. Patient noncompliance
9. Lab error
10. Viral infection

Question 284

Identify SPACE bugs and coverage (3)

• which inhibit cell wall
• DNA hyraxes
• 30S?

Answer 284

SPACE - serratia, pseudomonas, Acinetobacter, citrobacter, Enterobacter

BOX and One coverage with Ace in the Hole

1. Cell wall inhibition
   A. PCN; piperacillin, ticarcillin
   B. Cephalosporins; ceftazidime, cefepime
   C. Carbapenems; imipenem, meropenem, doripenem
   D. Monobactam; AZTREONAM (ACE In hole - if PCN allergy)
2. DNA gyrase
   - FLUOROQUINOLONES; ciprofloxacin, levofloxacin (use if allergic to PCN)
   - it prolongs QT interval
3. 30 S
   - Aminoglycosides; gentamicin, tobramycin, amikacin
   * cause Ototoxicity at peak and nephrotoxicity at trough

Question 285

Describe the general structure of penicillins and what drugs act against it and how?

**what bug do you need additional coverage for?

Answer 285

1. PCN structure ; House with garage and security system
   A. House; Thiazolidine ring
   B. Garage door; Beta-lactam ring
   C. Security system; Acyl side chain
2. Beta-lactamase inhibitor; irreversibly binds to beta-lactamase

** You need additional coverage for staphylococcus aureus

Question 286

Below is the MoA of what abx

A. Inhibits bacterial cell wall synthesis
- blocks crosslinking of adjacent peptidoglycan strands
- results in lysis
B. Penicillin-binding proteins are targets
- induce transpeptidases, transglycolases and D-alanine carboxykinase (peptidoglycan transpeptidase is inhibited)
C. Bactericidal

**identify 3 mechanisms of resistance

Answer 286

BETA - LACTAM INHIBITOR

Resistance

1. Beta lactamase production
   - staphylococcus, H.flu
   - Alterations in penicillin binding proteins
   - pneumococcus (strep pneumo), MRSA, enterococcus
2. Decreased penetration to site of action
   - Gram negative organisms only (porin channel penetration); prevents penicillin from going int original channel

Question 287

Absorption of Abx

1. What is timeline for penicillins to yield peak levels after ingestion?
2. Food delays and decreases absorption. Absorption is not decreased with what 3 abx?
3. Absorption depends on acid stability. Acid stability is divided into what 2 groups
   A. Penicillin VK, Oxacillin, Cloxacillin, Dicloxacillin, Nafcillin, Ampicillin, Amoxicillin
   B. Penicillin G, Methicillin, Carbenacillin*, Ticarcillin, Mezlocillin, Piperacillin

Answer 287

1. Penicillin peak 1-2 hours after ingestion
2. Absorption not decreased with Penicillin V, Amoxicillin, Carbenicillin (Pvac)
3. A. Acid stable; Pvocdnaa
   B. Acid labile; Pgmctmp

Question 288

Abx distribution

1. Identify organs that abx is well distributed to? (6)
2. WHat happens in these area; abcess s, middle ear, pleural, peritoneal, synovial fluids to inhibit bacteria
3. What organs is abx insoluble in lipid so poor distribution

Answer 288

1. Lung, liver, muscle, kidney, bone and placenta
2. Levels sufficient
3. Insoluble in lipid; unless inflammation is present there is poor distribution to BRAIN, CSF and PROSTATE

Question 289

Abx elimination

1. What is most important route of elimination
2. What is other route of elimination and what abx are eliminated here (3)
3. What equation to estimate renal function

Answer 289

1. Renal excretion - most important
   - adjustment for renal insufficiency is a must
   - allows for high conc in the urine
   - infants excrete penicillins at a slower rate due to immature transport systems
2. Biliary excretion; ampicillin, nafcillin and the antipseudomonal penicillins
3. Cockcroft-Gault Quation
   - (140-age) x (weight) / (serum creatinine) x (72)
   - multiply above by 0.85 if female

Question 290

Abx adverse effects

1. What is the most common adverse effect documented. Give examples
2. Identify types of #1
   ; IgE mediated vs IgM/IgG mediated
   **what rash is most common

3. Identify 3 major adverse effects of PCN 
#3 is • C-diff that stuck around lung enough that body trying to build protection inside of it  • Inflammation of the colon - ONLY SEEN WITH COLONOSCOPY  • Almost every antibiotic can cause this. Abx cause diarrhea

Answer 290

1. Hypersensitivity reactions
   - all penicillins have equal potential for inducing allergic reaction
   - hypersensitivity to one means probable hypersensitivity to all penicillins
2. Hypersensitivity may occur on first exposure or upon unknown re-exposure (med hx)
   A. IgE mediated - Immediate reaction (anaphylaxis)
   B. IgM or IgG mediated - delayed reaction (rash)
   **Maculopapular rash is most common
3. A.E
4. Eosinophilia
5. INTERSTITIAL NEPHRITIS e.g methicillin
6. Pseudomembranous colitis

Question 291

Identify Abx based on spectrum of activity (Be specific)

• gram negative organisms (streptococcus and some enterococcus)
• staph produce beta-lactamase - 99% resistant (penicillin binding protein changes)
• *Strep pneumonia resistance prevalent in some areas
• Gonorrhea resistance occurring

Answer 291

Penicillin G/VK

**must use Pen VK for oral administration (acid-labile)

Question 292

1. Identify class of penicillins

• IV; Methicilln, Oxacillin, Nafcillin. Nafcillin is hepatic elimination
• PO; Cloxacillin, Dicloxacillin

2. What does it cover (2)

Answer 292

1. Penicillinase Resistant Penicillins
   - Anti-staphylococcus penicillins
2. Cover Streptococcus and Beta-lactamase positive staph

• *If pt has MRSA, pls do not give these abx.
• Entire penicillin family cause interstitial nephritis

Question 293

1. What abx covers ENTEROCOCCUS
2. Belongs to what class
3. Spectrum covers/includes ? (5)
4. Identify 2 side effects of this class

Answer 293

1. Ampicillin (QID) / Amoxicillin (TID)
   QID is too many times a day so patient can forget. It is also less absorbed so have more side effects
2. AMINOPENICILLINS
   - Amino group allows for penetration into gram negative cell wall
3. Spectrum includes; (also covers some PEK bugs)
   - streptococcus
   - enterococcus
   - haemophilus (non beta lactamase producing)
   - salmonella/shigella (non beta lactamase)
   - proteus mirabilis, E.coli, +/- klebsiella
4. A. Hypersensitivity
   B. Diarrhea; take with food to decrease so
   - absorption not impaired in amoxicillin
   - ampicillin > amoxicillin

Question 294

Identify class of abx

• Good coverage of gram negative (increased permeability to cell wall)
• Side effect is SODIUM attached to it
• Only was good for UTI but not on market anymore
• activity includes; streptococcus, piddly/PEK, SPACE bugs; pseudomonas aeruginosa (high conc necessary)

2. Give 2 examples
   - which is more active against pseudomonas
3. Identify adverse effects of this class (3)

Answer 294

1. CARBOXYPENICILLINS
2. A. Carbenicillin
   - HIGH URINE CONCENTRATIONS
   - indanyl salt- stable oral form (Geocillin)
   - body normally can’t tolerate high dosages necessary for conc to treat systemic infections
   -market availability

B. Ticarcillin

• LOTS OF SODIUM RETENTION (avoid in HTN and CHF)
• Na+ load = 5.2 Med/gm
• 2 to 4 times more active than Carbenicillin against pseudomonas

3. Carboxypenicillin A.E
   - hypersensitivity
   - cause platelet dysfunction (dose dependent side effects)
   - Na+ overload

Question 295

1. Identify class of abx
   - mezlocillin
   - piperacillin
   - Na+ load = 2 Meq Na+/gm. Less than half of carboxypenicillin group per gram
2. Identify coverage (4)

Answer 295

1. UREIDOPENICILLINS
2. Spectrum
   A. Bacteroides fragilis (non beta lactamase producing strains)
   B. Streptococcus, enterococcus
   C. PEK bugs
   D. SPACE bugs
   - Enterobacteriaceae family; proteus, E.coli, klebsiella, enterobacter, serratia
   - SPACE bugs; pseudomonas aeruginosa, piperacillin and azlocillin 2-5x more active than Carbenicillin

Question 296

1. Beta lactamase inhibitors / penicillin combinations; gives extra coverage to what bugs?
   * what is not covered?
2. Give examples of combo products in #1 and when you will need beta lactamase inhibitor

Answer 296

1. Key additions to coverage
   - adds STAPHYLOCOCCUS coverage
   - adds ANAEROBES coverage (peptostreptococcus, bacteroides, clostridium)

**Only thing not covered here is atypicals (chlamydia, legionella, mycoplasma)

2. Combo products
   - Augmentin-amoxicillin/clavulanic acid
   - Unasyn-ampicillin/sulbactam
   - Timentin-ticarcillin/clavulanic acid
   - Zosyn-piperacillin/tazobactam

**Beta lactamase inhibitor will depend upon incidence of beta lactamase production

Question 297

Simplifying microbiology

1. Identify gram positive

2. Gram negative class 
A. Piddly 
B. Fence bugs 
C. SPACE 
D. Atypicals 
E. Anaerobes

Answer 297

1. Gram negative
   - streptococcus
   - staphylococcus
   - enterococcus
2. Gram negative
   A. Piddly
   - Haemophilus flu, morexella, Morganella, shigella, salmonella, Providencia, neisseria

B. Fence bugs (PEK)

• proteus
• E.coli
• Klebsiella

C. SPACE

• serratia
• pseudomonas
• Acinetobacter
• Citrobacter
• Enterobacter

D. Atypicals (CML)

• chlamydia
• mycoplasma
• legionella

E. Anaerobes (mouth - SI - LI)

• peptostreptococcus
• bacteroides
• clostridium

Question 298

Identify group of bacteria

• small GRAM NEGATIVE rods, can be pleomorphic
• facultative anaerobe
• most require ENRICHED media for isolation
• of this family, HAEMOPHILUS are most commonly isolated human pathogen

Answer 298

PASTEURELLACEAE

Question 299

1. Identify gram negative

• similar to bordetella pertusis
• blood loving
• relatively few species are pathogenic to humans
• colonize the UPPER RESPIRATORY TRACT in first few months of life

2. Identify species

Answer 299

1. Haemophilus Influenza

• Haemophilus = blood loving
• Indicates requirements for BLOOD FACTORS FOR GROWTH;
• Hemin or X factor; heat stable iron containing protoporphyrin essential for electron transport chain and important for aerobic growth
• V factor (think V=vitamin); coenzyme nicotinamide adenine dinucleotide NAD
• Both present in blood enriched media but must be gently heated to destroy the inhibitors of V factor; use heated blood agar, “chocolate” agar for isolation

2. Nearly all human disease due to strains of Haemophilus influenza. Other significant species;
   - H. Influenza biogroup aegyptis infection results in acute purulent conjunctivitis
   - H. Aphophilus and parainfluenza associated with endocarditis and infections in IMMUNOCOMPROMISED hosts

Question 300

1. Identify 2 strains of H.Influenza
   - what are major proteins in the blood
   - which cause invasive disease like meningitis
   - what does clonal mean
2. What cause infections of mucosal surfaces (localized)
3. What cause majority of Invasive disease
   - composed of what?
   - what account for 95% of all strains that cause invasive disease

Answer 300

1. 2 strains; 1 capsulated (typable) the other unencapsulated (non-typable)
   • Major proteins in the blood; albumin and LOTS OF COMPLEMENT
   • ENCAPSULATED go into the blood - INVASIVE disease e.g meningitis
   • CLONAL; means all the strains are the same (unlike strep pneumo that has 90 different types of capsule). H.flu only has 6 different strains (most common is type b strain)
2. Strains without polysaccharide capsules (non-typable) cause infections of mucosal surfaces (LOCALIZED)
   - OM, sinusitis, bronchitis, pneumonia
   - rarely disseminate
3. Capsular polysaccharide
   - encapsulated strains (typable) cause majority of invasive disease
   - composed of PRP (polyribitol phosphate)
   - can express 1 of 6 polysaccharide capsules
   - H.influenza type B (Hib) accounts for 95% of all strains taht cause invasive disease

Question 301

Haemophilus influenza; pathogenesis and immunity - mucosal colonization

1. Transmission
   - what most they overcome to colonize

• what promote bacterial binding to mucous?
• what damages ciliated cells
• what mediate direct adherence to nonciliated
  epithelial cells
• what cleave IgA
• Invasion into cells and subepithelial space
• what allow organisms to persist

Answer 301

1. Transmission from carrier to new host
   - colonization; must overcome nonspecific mucociliary defenses

• Outer membrane proteins (OMP) P2 and P5 promote bacterial
  binding to mucous
• LPS damages ciliated cells
• Adhesins and pili mediate direct adherence to nonciliated
  epithelial cells
• IgA proteases cleave IgA
• Invasion into cells and subepithelial space
• ***Binding and uptake of iron and heme allow organisms to persist

Question 302

Haemophilus influenza; pathogenesis and immunity - mucosal infections

1. What strain cause infection
2. How does direct movement of organisms occur
   - identify risk factors

Answer 302

1. Disease due to unencapsulated (non-typable strains)
2. Direct movement of organisms
   ◦ Through nasal ostia to the sinuses
   ◦ Eustachian tubes to middle ear to cause otitis media
   ◦ Down bronchi to cause bronchitis and pneumonia
   ◦ Risk factors cigarette smoke, allergic disease, and viral infection

Question 303

Haemophilus influenza; pathogenesis and immunity - invasive disease

• how does it get to site
• caused by what strain
• what is major virulence factor
• how do they invade mucosa
• severity of infection related to what?
• antibodies directed against?
• risk of meningitis and epiglottitis is increased in what patients?

Answer 303

• MUCOSA - BLOODSTREAM - DISTAL SITES
• Caused by typable strains (most Hib)
• Invade mucosa by separating apical tight junctions of columnar epithelium and moving intercellularly
• Bacteremia initially low in concentration but increases in matter of hours
• Polysaccharide capsule is anti-phagocytic and major
  VIRULENCE FACTOR
• Severity of infection related to rate of clearance of bacteria
  ◦ When bacterial conc. ≥ 104 /Ml metastatic seeding occurs
• Antibodies directed against the capsule stimulate
  phagocytosis and complement mediated activity
  ◦ Antibodies formed following natural infection, vaccination, or
  passive maternal transfer
• Risk of meningitis and epiglottitis increased in patients
  with no ANTI-PRP ANTIBODIES, COMPLEMENT DEFICIENCY, POST-SPLENECTOMY

Question 304

Identify clinical syndrome

• Prior to H.influenza vaccination, it was the most common cause of this disease
• Nonspecific signs and symptoms especially in younger children
  (1-3 day history of mild upper respiratory disease, irritability, fever and lethargy)
• older children may have headache photophobia and meningismus
• fulminant disease (rapid neurological deterioration)

**Identify
Complications? (5)
Mortality rate
Long term sequelae

Answer 304

Meningitis

Question 305

Identify clinical syndrome caused by Haemophilus influenza

• Cellulitis and swelling of supraglottic tissues
• can result in acute upper airway obstruction
• peak incidence of disease in 2-4 year olds
• RARE IN THE POST VACCINE ERA
• *
• abrupt onset of what?
• What is crucial for you to manage in this condition?

Answer 305

EPIGLOTTITIS

• abrupt onset of high fever, sore throat, dysphasia and sepsis
• Airway management is crucial; keep child calm, emergency nasotracheal intubation in OR (in case need of trach) by ENT or anesthesia

Question 306

Identify the clinical syndrome

• relatively uncommon form of Hib disease
• IN PRE-VACCINE era, it is seen mostly in children <2
• manifests as fever with; unilateral raised warm and tender area, may progress to violaceous hue (violet/purple lesions)

**what part of body is this mainly located? (3)

Answer 306

CELLULITIS

*Most located in cheek, periorbital region or neck

Question 307

Identify clinical syndromes of Hib

1. Typically caused by non-typable strains (3)
2. • caused by H.influenzae biogroup aegyptius
   • Epidemics during WARM MONTHS

3. Summarize clinical syndromes caused by H. Influenza (4)

Answer 307

1. Sinusitis, otitis and lower respiratory tract disease
2. Conjunctivitis
   - acute purulent conjunctivitis

3. HaEMOPhilus influenza 
A. Epiglottitis (can be cherry red in children, thumb sign on lateral neck) 
B. Meningitis 
C. Otitis media 
D. Pneumonia

Question 308

Identify laboratory diagnosis of H. Influenza

1. When do you have high index of suspicion?
2. When do you order blood culture?
   - other cultures that can useful?
   - you DO NOT perform throat cultures in what patients?
3. What will you see from gram stain?
4. What will you see from culture?

Answer 308

1. High index of suspicion especially in UNIMMUNIZED CHILDREN
2. Culture
   - obtain blood culture in any child with SUSPECTED INVASIVE DISEASE
   - CSF, pleural fluid, sputum cultures may also be useful
   - DO NOT perform throat cultures in patients with SUSPECTED EPIGLOTTITIS
3. Gram stain
   - gram negative rods
   - Pleomorphic, may appear as coccobacilli or filaments
   - (+) in 80% of patients with meningitis
4. Culture
   - chocolate or levinthal agar
   - 1-2mm smooth opaque colonies
   - satellite phenomenon; staph aureus excretes NAD or V factor allowing H.flu to grow as small colonies

Question 309

Treatment and prevention of Haemophilus influenza

1. Beta lactamase production
2. Vaccine?
3. Prophylaxis?

Answer 309

1. Beta-lactamase production
   - 3rd generation cephalosporins for SERIOUS infections
   - PCN (+) beta-lactamase inhibitor
2. Conjugated PRP vaccine
3. Antibiotic prophylaxis for close contacts with rifampin

Question 310

1. Identify gram negative diplococcus that cause meningitis

2. 10 species with 2 causing majority human disease - meningitidis and gonorrhoeae

Answer 310

1. Neisseria Meningitidis

2. Neisseria

Question 311

Identify group of pathogens/organisms

• consist of 5; last 4 are considered as uncommon gram negative bacteria
• normal part of the ORAL PHARYNGEAL microbiota; unusual cause of infective endocarditis
• most common gram negative cause of endocarditis among people WHO DO NOT USE IV DRUGS

**What is the treatment of choice?

Answer 311

HACEK pathogens

• Haemophilus
• Aggregatibacter (previously Actinobacillus)
• Cardiobacterium
• Eikenella
• Kingella

Tx for HÁČEK organisms in endocarditis;

• 3rd generation cephalosporins and beta lactam antibiotic ceftriaxone
• Ampicillin (PCN), combined with low dose gentamicin (Aminoglycoside) is another therapeutic option

Question 312

Identify the organism based in physiology and structure

• Similar in structure to strep pneumo but its is a gram negative organism (gram negative diplococci with flattened sides - coffee beans)
• grow best in CHOCOLATE MEDIA; complex/fastidious growth requirement
• They oxidize carbohydrates; useful in differentiating pathogenic strains

1. What is the major virulence factor which is the basis for serotyping?
2. Other virulence factors? (5)
3. What mediate attachment to host cells and invasion
4. What form channels for nutrients to enter

Answer 312

NEISSERIA

1. Polysaccharide CAPSULE is major virulence factor
   - basis for serotyping
2. Other virulence factors; Pili, Porin proteins, LOS (lipooligosacharide), IgA protease, Transferrin brining proteins
3. Pili - mediate attachment to host cells and invasion
   - pili gene can be turned on and off which may aid in detachment and transmission to another host/site
4. Porin proteins - form channels for nutrients to enter cell
   - PorA and PorB proteins
   - PorB can interfere with degranulation of neutrophils
   - PorB facilitates invasion to epithelial cells
   - PorB PIA antigen makes bacteria resistant to complement mediated serum killing

Question 313

Identify structural components of neisseria

1. • STRONG ENDOTOXIN activity
   • how is this different from structure in outer membrane of regular gram negative?
   • Neisseria release outer membrane blebs during rapid cell growth
2. • allows bacteria to compete with human hosts for iron
3. • cleaves the hinge region in IgA1

Answer 313

1. LOS (lipidooligosaccharide)
   - composed of Lipid A and core oligosaccharide
   - lacks the O-antigen polysaccharide of LPS
   - lipid A possess endotoxin activity
   - neisseria release outer membrane BLEBS during rapid cell growth
2. Transferrin binding proteins
   - binds HUMAN transferrin
   - allows bacteria to compete with human hosts for iron
   - specificity for human transferrin likely why strict human pathogen
3. IgA protease
   - cleaves the hinge region in IgA1

Question 314

Identify species of Neisseria

• human nasopharynx only natural reservoir (transmitted via respiratory and oral secretions)
• once respiratory tract colonized either; develop invasive disease, develop antibody and become immune
• Adhere to nonciliated columnar epithelial cells in nasopharynx via pili
• binding induces endocytosis into epithelial cells
• Penetrates epithelial barrier via phagocytic vacuoles (able to avoid intracellular death, replicate and migrate to subepithelail space)
• *
• what type of capsule?
• what increase risk for infection?

Answer 314

Neisseria MENINGOCOCCUS

• if antibody is insufficient and invasion occurs, individual may become bacteremic and progressively ill
• bacteria in blood may seed meninges and cause meningitis
• antibodies against polysaccharide capsule protective
• infects protected via passive transfer of maternal antibody that wanes by 6 months of age
• complement system important for bactericidal activity
• ***Patients with deficiencies of C3, C5, C6, C7, C8 at INCREASED RISK OF INFECTION

Question 315

Epidemiology of Neisseria Meningitis

1. Endemic?? Epidermics?
2. What serotypes are most common in US and Europe? Developing countries?
3. What is common in Africa? Mecca?
4. Natural carriers? Asymptomatic carriage?
   - carriage rates?
   - Transient carriage?
   - transmitted how?
   - disease most common where?

Answer 315

1. • Endemic disease occurs worldwide.
   • Epidermics common in developing countries
2. • Serotypes B,C, Y - most disease in US and Europe each causing about 1/3 of cases
   • A and W 135 predominate in developing countries
3. • Meningitis Belt in Africa
   • Outbreaks during pilgrimage to Mecca caused by A and W 135 (people are in close proximity to one another - increased risk of meningitis)
4. • Humans are only natural carriers
   • Asymptomatic carriage varies with rates <1% to 40%
   • Carriage rates highest for school age children, young adults, lower socioeconomic status
   • Carriage is transient with clearance following development of protective antibodies
   • Transmitted via respiratory droplets among people with prolonged close contacts
   • Disease most common in children <5, teenagers, young adults, elderly, those living in closed populations

Question 316

Identify condition

• abrupt onset with headache, meningeal signs and fever
• Younger children may have nonspecific signs such as fever and vomiting
• May occur with meningococcemia
• Mortality rate 100% untreated 10% treated
• Most common neurological complications; hydrocephalus, cranial nerve palsy, subdural effusion, cerebral edema, cerebral infarction

Answer 316

MENINGITIS

Question 317

Identify condition

• DIC, rash, fever
• Typical presentation; short history of URI symptoms, fever and rash
• several circulatory collapse with DIC and thrombosis of small blood vessels follow
• purpura and shock can occur within hours of initial presentation
• overwhelming shock and DIC may result in bilateral destruction of adrenal glands - Waterhouse - FRIDERICHSEN SYNDROME
• finding of petechiae or purpura in febrile child should increase index of suspicion

Answer 317

MENINGOCOCCEMIA

• finding of petechiae or purpura in febrile child should increase index of suspicion
• PURPURA FULMINANS (large hemorrhagic lesions)

Question 318

Primary meningococcal pneumonia

1. Most common manifestation where?
2. What serotype of Neisseria associated with pneumonia?
3. Other clinical syndromes (3)

Answer 318

Primary meningococcal pneumonia

• Most common manifestation of disease in MILITARY RECRUITS and 4.5% of disease in general population
• Y and W-135 associated with pneumonia
• Other clinical syndromes; CONJUNCTIVITIS, PHARYNGITIS and ARTHRITIS

Question 319

Laboratory Dx of Neisseria meningitidis

1. What is gold standard for diagnosis?
2. Which test is less useful if patient is pre-treated with Abx

Answer 319

1. CULTURE; gold standard for diagnosis
   - CSF, blood, petechiae
   - Blood culture alone is positive in 50% of patients who had received no prior abx
2. Microscopy
   - N. Meningitidis readily seen in CSF of patients with meningitis
   - Less useful if pt pre-treated with abx
   - Over decolonized S. Pneumoniae may be confused with N. Meningitidis on gram stain

Question 320

Identify treatment and prevention of Neisseria

• are they resistant by beta lactamase?
• which have intermediate sensitivity
• prophylaxis?

Answer 320

• Penicillin vs Ceftriaxone
• Resistance by beta lactamase; rare
• Penicillin binding proteins mutations with intermediate sensitivity; increasing
• prophylaxis to significant exposure; household, child and day care, barracks CPR, intubation
• rifampin, FQs, Ceftriaxone, spiramycin (not sulfa)

Question 321

Identify vaccinations for Neisseria

• required in which people
• 2 vaccines
• which one is for short term protection

Answer 321

A. Group specific capsular polysaccharide
B. A,C,Y, W135 (quadra-valent)
C. Do not cover B
E. Recommended at;
- 11-12 yrs of age, adolescents entering college, military recruits, travel, asplenic patients or complement deficiency

F. 2 vaccines

1. Polysaccharide (MPSV4); unable to stimulate t-cell dependent immunity to produce memory cells (only for short term protection - get it every year)
2. Conjugate (MCV4); polysaccharide capsule conjugated to diphtheria toxoid protein carrier ; longer lasting immunity although duration unknown, preferred vaccine

Question 322

▶ Haemophilus, blood-loving, X/V factors, blood enriched and chocolate media.
▶ Six capsule types (one strain type b, 95%), PRP, Hib vaccine,
capsule strain (invasive disease), unencasulated mucosal
infection.
▶ Localized vs invasive diseases, pediatric
▶ Neisseriaaceae, three genera, HACEK, IE for non-drug user, N.
meninigitidis, 13 serotypes, most often 4 serotypes,
polysaccharide major virulence factor
▶ Antibiotic resistance, mainly through PBP
▶ Group specific polysaccharide, quatravalent vaccine,

Answer 322

Summary of Haemophilus and Neisseria Infections

Question 323

Identify condition

• infects 1/3 of the world’s population. 8 million new cases occur each year, and approximately 2 million deaths each year.
• second only to HIV as a cause of death worldwide resulting from a single infectious agent.
• Nearly 6% of all infant death, and 20% of adult death
  are caused by this
• Two factors essential for its rapid spread are crowded
  living conditions and a population with little innate
  resistance.
• The fatality rate of untreated is 50%.
• A resurgence of new cases has set off a panic.

Answer 323

Mycobacterium TUBERCULOSIS

Question 324

Key facts about TB

1. What causes TB? (General xters?)
2. Trasmitted by? (2)
3. 2 forms
4. Damage to primary form result in formation of what? Proceeds to what in immunocompromised individuals?
5. Damage in secondary form?

Answer 324

1. Mycobacterium tuberculosis; slow growing, acid-fast obligate aerobe that invades macrophages
2. Transmitted by inhalation or ingestion
3. 2 forms
   A. Primary TB; usually mild disease
   B. Secondary TB; disease caused by deactivation of dormant organisms
4. Damage in primary form; formation of GRANULOMAS followed by CASEOUS NECROSIS. In immunocompromised individuals, this proceeds to MILIARY TB with dissemination to other body sites, bone marrow, spleen, kidney and CNS
5. Damage in secondary form; caused by delayed-type hypersensitivity reaction to reactivated organisms

Question 325

1. Mycobacterium TB has a unique component in cell wall called?
   - major type?
2. Need oxygen? Gram stain?
3. Infections caused by?
4. Resistance to? (2)
5. rate of growth?

Answer 325

1. WAXES - hydrocarbon/hydrophobic in cell wall
   - major type of waxes is MYCOLIC ACIDS
   - Acid fast unique acidic waxes surround bacterium composed of Mycolic acids (beta hydroxy fatty acids linked to murein). Affects permeability of cell
2. An obligate aerobic rod with Gram (+) like cell wall
3. Infections caused by aerosol droplet
   - transmission occurs when there is prolonged close contact between a susceptible person and a person with an active case of TB
4. Resistance to drying and chemicals
   - highly resistant to germicides
5. Grows very slowly in vitro and in vivo
   - slow growth generation time is about 13 hours
   - may be a result of inability of nutrients to get into the cell
   - lab cultures are usually incubated up to 8 weeks

Question 326

Mycobacteria Cell Envelope

• similarity to gram positive?
• similarity to gram negative?
• cell wall of mycobacteria unique in what?

Answer 326

• No outer membrane so most closely related to gram positive
• Peptidoglycan layer is not as thick (like gram negative)
• Cell wall of mycobacteria is unique in its LIPID COMPOSITION
• multiple unique lipid-based molecules

Question 327

1. In Mycobacterium TB, what makes up 30-60% dry weight of cell wall
2. 30% of bacterial genome make?
3. What are both 1 and 2

Answer 327

1. LIPIDS
2. Waxes (Mycolic acids)
3. Both structural components (lipids and Mycolic acids) are virulence factors
   - activate or suppress the immune system

• immune stimulation; formation of granulomas
• receptors for invasion of macrophages and dendritic cells
• immune escape suppress DC maturation, T cell responsiveness
• Immune evasion mask PAMPS in cell wall avoiding recognition
• Survival inside macrophages; PREVENT PHAGOLYSOSOME MATURATION

Question 328

Differentiate primary and secondary (reactivation)mTB

**Reactivation happens in what part of the lungs?

Answer 328

1. Primary TB
   - inhalation of bacteria - bacteria reach lungs and enter resident alveolar macrophages - bacteria multiply within macrophages - lesion begins to form - lesion liquefies (cough up in sputum) - spread to other organs and into blood - death
2. Reactivation TB
   - inhalation of bacteria - bacteria reach lungs and enter resident alveolar macrophages - bacteria multiply within macrophages - lesion begins to form - immune suppression - reactivation (bacteria stop growing and lesion calcifies)

***Reactivation happens in the APEX OF THE LUNGS

Question 329

Diagnosis of M. TB

1. Test ‘
2. Interpretation
   - 2 factors

Answer 329

1. TST application; patch test (type IV hypersensitivity)
   - tuberculin 0.1 ml; PPD (purified protein derivative)
   - intradermal placement; injection should produce a pale elevation of skin 6-10 mm in diameter
   - TST detects T cell response to M. TB antigens (APC and memory T cell interact in lymph node and then allow for T cell proliferation) - cause red skin induration
2. TST Interpretation
   - 2 factors; measurement (5mm, 10mm, 15mm) and risk of progression to active TB disease
   - the higher the risk for progressing to active TB disease, the lower the measurement cutoff is for interpreting TST as positive test

Question 330

1. What is an alternative to TST for TB test
   - used in people who has the BCG vaccine to prevent false positive on patch skin test
   - there is no false positives with this test
2. • how is this test similar to TST
   • how is it different
   • what does test measure

Answer 330

1. IGRA (Interferon - Gamma release assay)
   - similar to TST, IGRAs detect a memory T cell response to MTB
   - blood test instead of skin test
   - measure the amount of IFN-gamma produced by T cells exposed to Mtb antigens
   - Specific TB antigens are used instead of undefined mixture in PPD
   * Reduce false-positive results
   * Distinguish from response to BCG

Question 331

How do IGRAs distinguish between infection with Mtb vs BCG

Answer 331

• The BCG vaccine strain is an attenuated M.bovis isolate that has lost several genomic regions important for granuloma formation and persistent infection
• One region, RD1, contains the genes for the ESX-1 secretion system and 2 secreted effector proteins; ESAT-6 and CFP-10
• IGRAs use peptides from Mtb antigens (ESAT-6 and CFP-10) that are missing in BCG (and most NTMs) to stimulated T cells

Question 332

1. What is the gold standard for testing active TB disease
2. What provide early indication of active Tb
3. What is important for diagnosing extra pulmonary disease
4. What techniques are improving speed and sensitivity of identification

Answer 332

1. GOLD STANDARD is CULTURE
   - shows definitive infection
   - allows examination of bacilli for drug susceptibility

• But slow growth (4-6 weeks)
  2. AFB sputum smear can provide early indication of active Tb
  3. TISSUE SAMPLES (biopsies, lumbar puncture, urine culture) are important for diagnosing extra pulmonary disease

4. PCR amplification and sequencing techniques are improving speed and sensitivity of identification
   (PCR gives more accurate diagnosis)

Question 333

Identify the following drugs for TB treatment.
** how do you use them

1. inhibit RNA polymerase - prevent transcription; however bacteria can become resistant
2. Inhibit Mycolic acid
3. treat active disease - target unknown. Effective to kill slowly divine bacteria
4. treat active disease and when DNA is resistant

Answer 333

DRUGS FOR TB; long term treatment - 3 to 4 drugs for 2 months and the 2 drugs (INH and RIF) for 4 months

1. Rifampin; inhibit RNA polymerase - prevent transcription; however bacteria can become resistant
2. ISONIAZID; Inhibit Mycolic acid
3. PZA; treat active disease - target unknown. Effective to kill slowly divine bacteria
4. Ethambutol; treat active disease and when DNA is resistant

Question 334

Identify medication

• CORNERSTONE of TB treatment
• used for treating LTBI (latent TB Infection) and active disease
• diffuse well into host cells and into Mtb
• Inhibits enzyme important for producing MYCOLIC ACIDS in the cell wall
• Rapid killing (bactericidal) for bacteria that are metabolically active; slower killing for non-dividing bacteria. *thus need long treatments

Answer 334

ISONIAZID (INH)

Question 335

Identify medication

• used for treating LTBI and active disease
• lipophilic so it diffuses well into Mtb
• binds to bacterial RNA POLYMERASE, preventing transcription of DNA into RNA (highly bactericidal)
• combination with INH allowed reduction of treatment times
• drug interactions

Answer 335

RIFAMPIN (RIF)

Question 336

Identify medication

• used for treating active disease
• MoA not clearly defined but may disrupt the plasma membrane
• can kill in acidic environments
• Effective at killing slowly dividing/non dividing bacilli
• important complement to INH and RIF. Decreases duration of treatment by 2 months
• M.bovis is intrinsically resistant to this medication

Answer 336

PZA (Pyrazinamide)

Question 337

Identify medication

• used for treating active disease when resistance to INH is suspected
• MoA is to inhibit cell wall synthesis by blocking arabinogalctan polymerization
• An important side effects is that it can cause OPTIC NEURITIS

Answer 337

ETHAMBUTOL (EMB)

Question 338

What is treatment regimen (first line drugs) for TB treatment

• pulmonary TB? Extrapulmonary disease? LTBI?

Answer 338

1. For pulmonary TB
   - 3 or 4 drugs for two months followed by 2 drugs for four months
   - RIF, INH, PZA and EMB for two months
   - INH and RIF for four months
2. DOT is important to ensure adherence and reduce resistance (when you take medication in front of MD or nurse)
3. For extrapulmonary disease or with HIV treatment may be longer
4. For LTBI; one drug is used
   - usually INH for 9 months

Question 339

1. Tubercuosis is the leading cause of death in what subset of people

Answer 339

1. HIV positive
   - TB is leading killer of HIV positive people causing one fourth of all HIV related deaths
2. HIV infected
   - 30 times more likely to progress to TB disease
   - 40% develop TB disease 2-3 months after exposure
   - TB increases risk of HIV progression
3. Associated with multi-drug resistant TB

Question 340

Identify teh following resistance

1. Resistant to 1 drug
2. Resistant to INH + RIF
3. Resistant to INH + RIF + second line drugs

Answer 340

1. DR-TB; resistant to one drug
   - drug resistant Mtb is a result of selection of naturally resistant bacilli from a large population of tubercle bacilli
   * Improper use of TB medications; Non-adherence, inadequate dose of drugs, inappropriate single drug therapy
2. MDR TB
   - resistant to INH and RIF
3. XDR TB
   - resistant to isoniazid and rifampin + a FLUOROQUINOLONES + one injectable second line agent (kanamycin, amikacin, capreomycin)

Question 341

Identify

•Grow slightly faster than MTB, Acid-Fast bacilli found in macrophages
•Found worldwide in soil and water. U.S.: Southeast, Pacific coast,
and north-central regions.
•Second only to TB in significance and frequency.
•MAI is the most common cause of mycobacterial disease in AIDS
patients in the US (terminal stages of their immune disorder).
•Causes systemic infections in HIV patients.
•Diagnosis made most readily by blood culture

Answer 341

MAI (Mycobacterium Adium-intracellulare complex)

• *Avoid tap water if you have HIV - you can develop TB
• a lot of HIV people are infected with MAC/MAI
• it is all because of the cell wall waxes (they are hydrophobic so they clump together)

Question 342

Identify

• Gross specimen of lung showing the cut surface covered with white nodules, which are miliary foci of TB
• used specifically for HIV people

Answer 342

MILIARY TB

- MILIARY means tiny spread in tissues

Question 343

Identify species of mycobacterium

• Photochromogenic mycobacterium forming a yellow pigmented colonies following 2 weeks of incubation in the presence of light
• More prevalent since Mtb has declined. Most common in Il, Ok,Tx. affecting urban residents. 3% of mycobacterial infections in U.S.
• Causes cavitary pulmonary disease, cervical lymphadenitis and skin Infections. HIV patients with CD4 counts less than 200cells/ul
• PPD positive, resembles tuberculosis
• Prolonged chemotherapy with isoniazid, rifampin, and ethambutanol

Answer 343

Mycobacterium kansasii

Question 344

Identify species of mycobacterium

***What are 2 different presentations to know?

• Rare in U.S. (~250 cases/yr) 12 million worldwide. 62% in Asia,
  34% in Africa. Fewer than 10% of U.S. cases are U.S. natives. Largest number of cases in California, Hawaii, Texas, and Louisiana.
• Endemic disease has been demonstrated in armadillos.
• Unable to be grown on laboratory medium. Hence, laboratory
  confirmation requires histopathology consistent with clinical disease And skin test reactivity to lepromin or the presence of acid-fast
  bacilli in skin lesions.

Answer 344

Mycobacterium leprae (causes leprosy)

• you can’t grow leprosy in vitro
• 2 clinical presentations
  1) Tuberculoid leprosy; milder and self limiting disease (CMI - Th1)
• red blotchy lesions with anesthetic areas. Low infectivity

2) Lepramatous leprosy; severest form of leprosy (NO CMI - Th2)

Question 345

Identify the 2 types of leprosy

1. • milder form
   • red blotchy lesions with anesthetic areas Cell-mediated response-Th1.
   • Infectivity-Low
2. Multibacillary. Growth of bacteria is relatively unimpeded. Lesions show dense infiltration. Large numbers of bacilli reach bloodstream.
   •Skin lesions are diffuse, extensive, depiliated, extensive tissue
   destruction
   •Cell mediated immunity is deficient Th2 response
   •Infectivity-High •Analogous to miliary TB •Nonreactive to lepromin

Answer 345

1. Tuberculoid leprosy

2. Lepromatous leprosy

Question 346

What is the treatment of leprosy

Answer 346

• Dapsone, rifampin, and clofazimine
for a a minimum of 2 years.

• Control effected by prompt recognition
and treatment of infected people.

Question 347

• Waxes in cell wall (G+ve like), acid-fast, aerosol droplet, alveolar macrophages, primary and secondary TB, granulomas, T-cells (Th1, IFN-g), fused macrophages, caseous necrosis, disseminated TB

• Skin test, delayed type hyper-sensitivity, induration, IGRA,
Four drugs, DR, MDR, XDR, HIV vs TB, first line and second
line drugs.

• MAI, HIV, Miliary TB, Tuberculoid (CMI) vs. Lepratomous (no
CMI) leprosy. Th1 vs Th2 response.

Answer 347

Summary of Mycobacterium infections

TB and leprosy

Question 348

Identify box and One therapy

• coverage
• MoA
• what to use when you have PNC anaphylaxis allergy

Answer 348

1. Box and One therapy; covers the resistant SPACE bugs (serratia, pseudomonas, Acinetobacter, citrobacter, enterobacter)
   - you use more than one drug (different mechanism of action to kills the bug)

A. Cell wall inhibitors =

• PNC; piperacillin (pip/tazobactam - zosyn), ticarcillin (ticar/clauvulanate - timentin)
• Cephalosporins; ceftazidime (3rd gen), cefepime (4th gen)
• Carbapenems; Imipenem (seizure), moropenem, doripenem
• Monobactam (ace in hole); Aztreonam (anaphylaxis to PCN)

B. DNA gyrase
- FLUOROQUINOLONES (FQN); ciprofloxacin, levofloxacin

C. 30 S
- Aminoglycosides (AG); Gentamycin, Tobramycin, amikacin

**Ace in hole = Aztreonam (Anaphylaxis)

Question 349

Identify the structure of cephalosporin
**compare with penicillin

**Identify the qualities of the Acyl side chains (R1 and R2)

**what can counter beta lactamase sensitivity?

Answer 349

1. Cephalosporin structure
   - House; Dihydrothiazine ring
   - Garage; Beta-lactam ring
   - Security system; Acyl side chain (R1)
   * * Similar to penicillin except the house is thiazolidine ring

R1; spectrum of activity, PBP affinity, BETA LACTAMASE SUSCEPTIBILITY
R2; Stability, metabolism, adverse effects, drug interactions, protein binding, half life

**Beta-lactamase inhibitor (like clavulanic acid) irreversibly binds to a beta-lactamase; that it why it is good to combine both drugs to treat staphylococcus aureus

Question 350

Describe pharmacokinetic properties of Cephalosporins

1. Absorption
   - prodrug?
   - what enhance absorption?
2. Distribution
   - what gen of cephalosporins is great choice for meningitis
3. Metabolism/excretion
   - 2 forms of excretion
   - most use which excretion?
   - what are the 2 exceptions?

Answer 350

1. Absorption
   A. Oral agents; rapidly and completely absorbed
   B. Oral cephalosporins are available as prodrug esters and non esterfied compound. Prodrug esters;
   - Cefuroxime axetil (ceftin 2nd gen)
   - Cefpodoxime projectile (vantin P.O 3rd gen)
   *Hydrolyzed in intestines to an active drug
   *FOOD enhances absorption
2. Distribution
   A. well distributed to a variety of body tissues and fluids
   B. CSF penetration especially with inflamed meninges
   - 3rd generation cephalosporins are great choices for various bacteria that cause meningitis (Ceftriaxone)
   - Required high dose to be used (4x normal dose - ceftriaxone)
3. Metabolism/Excretion
   A. Renal excretion; all cephalosporins except 2.
   - you need dosage adjustments in patients with renal insufficiency
   B. Hepatic elimination; ceftriaxone, cefoperozone

***Following an IV infusion on the 5th generation, Ceftaroline fosamil (pro-drug) is rapidly converted by plasma phosphateases into an active ceftaroline

Question 351

1. Identify MoA of cephalosporins

- similarity to PCN?

Answer 351

1. MoA (very good because they get into tissues - used for meningitis and CHF)

A. Binds to PBPs (penicillin binding proteins); inhibits crosslinking of peptidoglycan strands

• cephalosporins are like PCN in that they mimic D-ala-D-ala and are incorporated into the active site of transpeptidase
• bind to PBP (transpeptidase) and form an irreversible covalent bond with a serine of the enzyme and the cross-bridging is halted
• CIDAL activity since the microorganisms CAN NOT survive without a formed cell wall

B. Efficacy of each cephalosporin is related to PBPs

C. Can be susceptible to some beta-lactamases

D. Beta-lactam ring is unstable in an acid medium

Question 352

1. Identify adverse effects of cephalosporins (6)

• hypersensitivity?
• hematology?
• alcohol?
• GI?
• renal?
• Immunologic?

Answer 352

1. Hypersensitivity reaction
   - 5-15% cross reactivity with penicillins; generally considered safe in non-IgE mediated (anaphylaxis) PCN allergic patients (DO NOT USE)
   - rash, drug fever
2. Hematology; BLEEDING
   - associated with these cephalosporins that have a N-methylthiotetrazole (NMTT) side chain (cefamandole, cefoperazone, cefotetan) due to HYPOPROTHROMBINEMIA (disturbance in Vit K dependent clotting factors by blocking the Vit K epoxide reductase)
3. Alcohol, disulfiram-like intolerance; similar effect of Antabuse
   - Agents with NMTT side chain (cefamandole and cefaperazone)
4. Gastrointestinal
   - Diarrhea
   - Pseudomembranous colitis (overgrowth of toxin-producing C.diff)
5. Renal
   - INTERSTITIAL NEPHRITIS (rare)
6. Immunologic
   - Serum sickness in children; cefaclor (ceclor - 2nd generation)

Question 353

Identify 3 drug interactions with cephalosporin

Answer 353

1. Warfarin
   - potentiation of anticoagulant effects
2. Alcohol
   - disulfiram like reaction
   - Agents with NMTT side-chain only
3. Probenecid
   - Prolongs excretion in cephalosporins that have TUBULAR SECRETION

Question 354

Identify medications in cephalosporin generation (5) - common oral products and common parenteral products

• *what are the only 2 that cover ANAEROBES
• *which covers SPACE bugs except pseudomonas
• *which covers pseudomonas
• which gen have both oral and parenteral?
• which have only parenteral?

Answer 354

1. First (1st gen)
   - Common oral; *Cephalexin (keflex), cefadroxil (duricef)
   - parenteral (IV); *Cefazolin (Ancef)
2. Second (2nd gen)
   - oral; *cefuroxime (ceftin), cefprozil (cefzil), cefaclor (ceclor)
   - parenteral; *Cefuroxime (zinacef)

• *2nd gen CEPHAMYCINS (cover anaerobes - ten fox)
• oral; N/A
• parenteral; *CeFOXitin (mefoxitin), *CefoTETAN (cefotan)

3. Third (3rd gen); first group covers SPACE bugs except pseudomonas
   - oral; cefixime (Suprax), cefdinir (omnicef), cefopodoxilme (vantin)
   - parenteral; *CEFTRIAXONE (ROCEPHIN), Cefotaxime (claforan)

• *3rd gen ANTIPSEUDOMONAS; covers pseudomonas
• oral; N/A
• parenteral; *CEFTAZIDIME (FORTAZ), cefoperazone (cefobid)

4. Fourth
   - oral; N/A
   - parenteral; *CEFEPIME (MAXIPIME)
5. Fifth gen
   - oral; N/A
   - parenteral; ceftaroline (teflaro)

Question 355

What is the coverage (spectrum of activity) of cephalosporin

1. As generations increase, what coverage increases?
2. Hat 4 groups do cephalosporins not cover generally?
   Give exceptions

Answer 355

1. As generations increase, GRAM NEGATIVE coverage increases
2. Cephalosporins generally DO NOT COVER;
   A. Enterococcus (except CEFTAROLINE - 5th gen; another drug that cover enterococcus is amoxicillin
   B. MRSA (except CEFTAROLINE - 5th gen)
   C. ATYPICALS (CML); Chlamydia, Mycoplasma, Legionella
   D. Listeria monocytogenes

Question 356

IDENTIFY coverage (spectrum of activity) of cephalosporin (From 1st to 5th gen)

A. Gram (+); excluding enterococcus
B. Gram (-)
C. Anaerobes (bacteroides)

• *which has poor gram (+) coverage but good gram (-) coverage including pseudomonas?
• Which cover anaerobes?
• which cover staph, strep, ENTEROCOCCUS (gram +) and SCE gram (-)
• *which cover weak piddly gram - but also E.coli only from PEK
• *which 2 gens cover SPACE bugs

Answer 356

1. First generation; Oral - CEPHALEXIN (keflex), IV - CEFAZOLIN (Ancef)
   A. Gram (+) no enterococcus; staph and strep
   B. Gram (-); minimal. Piddly and E.coli
   C. Anaerobes (bacteroides); No
2. Second; Oral - CEFUROXIME axetil (ceftin), IV - CEFUROXIME (Zinacef)
   A. Gram (+); Staph and strep
   B. Gram (-); YES - piddly and PEK (H. Flu, M. Cat- morexella, proteus, E.coli, klebsiella - PEK)
   C. Anaerobes (bacteroides); No

2.2. Second (cephamycins); No oral, IV - ten fox (CEFOXITIN and CEFOTETAN)
A. Gram (+); staph and strep
B. Gram (-); YES - H.flu, M.cat, PEK
C. Anaerobes; YES (ten fox kill anaerobes)

3. Third; IV - CEFTRIAXONE (rocephin)
   A. Gram (+); strep
   B. Gram (-); Yes - SACE (no pseudomonas)
   C. Anaerobes; No

3.2. Third (antipseudomonas); IV - CEFTAZIDIME (FORTAZ)
A. Gram (+); POOR
B. Gram (-); Yes - SPACE
C. Anaerobes; No

4. Fourth; IV - CEFEPIME (MAXIPIME)
   A. Gram (+); staph and strep
   B. Gram (-); Yes - SPACE
   C. Anaerobes; No
5. Fifth; IV - CEFTAROLINE (TEFLARO)
   A. Gram (+); staph, strep and *ENTEROCOCCUS
   B. Gram (-); SCE (no pseudomonas or Acinetobacter)
   C. Anaerobes; No

Question 357

Identify indications/uses of cephalosporins (8)

• 2 types of pneumonia? Which pneumonia type can’t it cover? (What will cover it)
• which can cross CSF
• soft tissues? (Mild vs severe)
• surgery?
• low neutrophils?
• cardiac infection?
• sex?

Answer 357

1. CAP (community acquired pneumonia)
   - 3rd gen (ceftriaxone)
   - *remember they do not cover atypical pneumonia (add macrolide, doxy/tetra or FQN to do so)
2. Nosocomial pneumonia (CEFTAZIDOME - 3rd gen antipseudomonas, CEFEPIME - 4th gen)
   - consider double coverage if SPACE bugs are involved
3. Meningitis (CEFTRIAXONE)
   - 3rd gen (use HIGHER DOSE)
4. Skin soft tissues
   - 1st gen (Oral - Cephalexin, IV - cefazolin); staph/strep (simple CELLULITIS, Non - DM)
   - Cephamycins (ten fox) or 3rd/4th gen for severe cases or diabetic patients (gram +/-/anaerobes)
   - ceftarolin 5th gen (covers MRSA if MIC <1.0)
5. Surgical prophylaxis
   - Cefazolin; long t1/2; covers staph (convenient dosing for OSTEOMYELITIS/MSSA SEPSIS)
   - Cephamycins; Abdominal/GI surgeries
6. Febrile Neutropenia (ALC = % neutrophils x WBC)
   - Ceftazidime or Cefepime +/- vancomycin
   * cefepime covers staph and strep of which ceftaz is poor
   * Vancomycin covers staph (and MRSA), strep, enterococcus
7. Endocarditis (depending on organisms)
8. STD
   - Neisseria resistant to Penicillin

Question 358

Identify the 4 components of carbapenems and their structures

**which is a carbacephem beta lactam agent (sulfur replaced by carbon)

• *main adverse effect
• *cross reactivity with what drug?

Answer 358

DIME (Dori, Imi, mero, erta)

1. Doripenem
2. Imipenem
   - carbacephem beta lactam agent; sulfur replaced by carbon
3. Meropenem
   - Methyl group at C1; no renal degradation
   - C2 substitution; dimethylcarbamylpyrrolidinethio side chain (increased gram negative activity)
4. Ertapenem

• *SEIZURES - main adverse effect
• • 10% cross reactivity is between carbapenems and penicillins (don’t use if you have anaphylaxis to PCN)

Question 359

Identify major adverse effects of the following drugs

1. All abx
2. PCN and cephalosporins
3. DIME
4. PCN that cause sodium retention

Answer 359

1. All Antibiotics
   - C.Diff; lead to pseudomembranous colitis
2. PCN and cephalosporin
   - cause INTERSTITIAL NEPHRITIS; first seen in methacillin
3. DIME
   - SEIZURES
4. Ticarcillin (against SPACE bugs)
   - do not use in CHF patients

Question 360

Pharmacokinetics of Carbapenems

1. MoA
2. Which has the longest half life? Allows for?
3. Which has extensive renal metabolism? What is added to prevent renal metabolism?

Answer 360

1. MoA; binds to PBP (penicillin binding protein) resulting in CIDAL EFFECT
2. ERTAPENEM (Invanz); has the LONGEST HALF LIFE
   - allows once daily administration
3. IMIPENEM (primaxin) only
   - Extensive renal metabolism by the brush border enzyme dehydropeptidase-1
   - CILASTATIN added to Imipenem to prevent renal metabolism (doesn’t add coverage it just increase kinetic properties)

Question 361

Identify adverse effects of Carbapenems (3)

• main adverse effect
• cross reactivity
• hematologic

Answer 361

1. Seizures
   - focus on IMIPENEM (primaxin)
   - epilepsy/seizure hx/increase risk of seizures (medications/ETOH use)
   - must reduce dose for renal insufficiency
2. Cross Allergenicity w/ PCN
   - 5 to 15%
3. Hematologic
   - Anemia, leukopenia, thrombocytopenia

Question 362

Identify spectrum of activity of carbapenems

Differences in DIM vs E

• all cover what? (DIME is first line of defense against what?)
• most narrow coverage?
• newest DIM drug that covers SPACE and anaerobes
• which has no enterococcus or SPACE bugs?

3. Indications/use (4)

Answer 362

**DIME is first drug of choice to cover ESBL (extended spectrum beta lactamase; staph, H. Flu etc)

1. DIM (doripenem, Imipenem, Meropenem)
   - staph, strep and ENTEROCOCCUS
   - SPACE bugs
   - Anaeroboes
   - ESBL organisms (PEK)-resistant bugs
   - Doripenem is the newest on the market
2. Ertapenem (Invanz)
   - similar to amp/sulbactam (unasyn) coverage except NO ENTEROCOCCUS COVERAGE
   - staph/strep
   - anaerobes
   - ESBL organisms (PEK); MOST NARROW ESBL COVERAGE
   - Q 24hrs dosing
3. Reserve use for;
   - Serious/life threatening illness
   - Multi-organism infections
   - Acute Necrotizing pancreatitis
   - ESBL organisms (unique coverage)

Question 363

Identify medication

• Low cross reactivity with penicillin except you have anaphylaxis? Use this drug if you have anaphylaxis rxn to PCN
• Only covers GRAM NEGATIVE space bus
• Only for patients with severe anaphylaxis from penicillin

Answer 363

AZTREONAM (Monobactam antibiotic)

A. cross reactivity with penicillin is VERY RARE
B. GRAM NEGATIVE coverage only
- touted originally as a safe Aminoglycosides
- compare coverage to ceftazidime
C. Serious gram negative infections or PCN allergic patients (IgE mediated reactions)

• *Useful in treating NOSOCOMIAL INFECTIONS caused by multiple organisms
• *CAP with risk factors for pseudomonas (bronchiectasis)
• *HAP with severe PCN allergy (late onset or risk factors for MDR pathogens)

Question 364

This is the structure and chemistry of what antibiotic

• Aminoglycosidic aminocyclitols
• 6 membered aminocyclitol ring (amino containing the nonamino-containing sugars attached to ring by glycosidic linkages)

Answer 364

AMINOGLYCOSIDES

Question 365

Identify MoA of Aminoglycoside

1. Binds to what part of cell?
   - gradient decreased in what environment?
2. Irreversibly trapped where?
   - AG binds to what ribosomal subunit
   - do they enter cell?
3. Cidal or static?
4. Time or concentration dependent killing?

Answer 365

1. Aminoglycoside binds to OUTER MEMBRANE of cell
   - results in rearrangement of LPS (lipopolysaccharide)
   - uptake is energy dependent
   - source of energy is an ELECTROCHEMICAL GRADIENT
   - Gradient is decreased in an ANAEROBIC ENVIRONMENT
2. Once across the membrane, the drug is irreversible trapped into BACTERIA CYTOPLASM
   - AG binds to the 30S and 50S ribosomal subunit leading to; decreased protein synthesis and misreading of mRNA
   - very high intracellular concentrations
3. BACTERICIDAL
   - although mechanism appears static, its action is cidal - Not fully understood
4. CONCENTRATION dependent killing with PAE
   - after exposure to inhibitor concentrations of AMGs, continued killing occurs

Question 366

Pharmacokinetics of Aminoglycoside

1. Absorption
   - good or poor absorption from GI tract?
2. Distribution
   - vascular space vs lungs vs serum vs CSF
3. Excretion
   - 99% unchanged via?

Answer 366

1. Absorption
   - poorly absorbed from GI tract
2. Distribution
   - distributed freely into vascular space
   - concentrations in the lungs are 25-50% of those achieved in the serum
   - distribution to CSF only 20% with inflammation; better in neonates (immature BBB)
3. Excretion
   - 99% unchanged vis GLOMERULAR FILTRATION

Question 367

1. Identify 4 major systemic infections that ahminoglycosides treat (also has SPACE bug coverage)
2. What conditions do you see the following alterations in pharmacokinetics
   A. Decreased Vd and Ke
   B. Change in Vd
   C. Decreased Ke, change in Vd
   D. Decreased Vd and creatinine production

Answer 367

1. A. Amikacin (**highest peak and trough)
   B. Gentamicin
   C. Tobramycin
   D. Neomycin (oral suppressant for GI surgery)
   **2 hours half life in first 3, 3 hour half life in neomycin, renal elimination

2. Alterations in pharmacokinetics 
A. Elderly 
B. Critically Ill (dehydrated or volume overload) 
C. Renal disease 
D. Cachexia/Malnourished

Question 368

1. Identify adverse effects of aminoglycosides (4)

Answer 368

1. Local reactions; thrombophlebitis
2. Nephrotoxicity; 0-50%
   - too high TROUGH
3. Ototoxicity; impairment of 8th cranial nerve
   - too high PEAKS
4. Neuromuscular blockade (rare); use caution when using with neuromuscular blocking agents which can caused PROLONGED PARALYSIS

Question 369

Identify spectrum of activity of Aminoglycosides

• gram neg?
• gram pos?
• space?

**Which AG has little or no activity for these organisms?

Answer 369

1. Gram Positive
   - staphylococcus spp. Sensitive
   - Enterococcus; (SYNERGY), common combination = ampicillin + gentamycin
   * *Only used for synergy with most gram positive organisms
2. Gram Negative (Space bugs)
   - piddly
   - PEK
   - SPACE

**KANAMYCIN has little or no activity. For these organisms

Question 370

Identify indications/use of Aminoglycosides

1. Serious gram positive or negative?
2. Specific uses? (2)
3. Oral AGs **Neomycin (3)
4. Topical AGs.

Answer 370

1. Serious GRAM NEGATIVE INFECTIONS
2. Specific uses of streptomycin/gentamicin
   - TB (streptomycin - RIPS vs RIPE)
   - Brucellosis (gentamicin + TCN or chloramphenicol)
3. Oral Aminoglycosides
   - Neomycin; suppress intestinal bacteria flora for ELECTIVE COLORECTAL SURGICAL PROPHYLAXIS
   - Neomycin; Decreases the number of ammonia-forming bacteria in HEPATIC COMA
   - Neomycin; reduces cholesterol absorption in HYPERLIPIDEMIA
   - Paromomycin; intestinal amebiasis - tapeworm
4. Topical Aminoglycosides
   - Eye, ear and skin infections

Question 371

What the different types of dosing treatment with aminoglycosides

1. Individualization of dose (3)
   - most accurate?
   - lowest toxicity and failure rate?
   - less accurate?
   - acceptable for initial dosing?
2. What is the basis of once daily dosing
   - rely on what effect?
   - effect on kidney?

*therapeutic index?

Answer 371

1. Individualization of Dose
   A. Pharmacokinetic principles
   - most accurate method
   - lowest toxicity and lowest failure rates
   B. Trial and Error
   - least accurate method
   - Highest toxicity and highest failure rates
   C. Nomograms
   - substantial variations exist in concentrations achieved compared to predicted values
   - Acceptable fo initial dosing, adjustments made on peaks and troughs obtained
2. Once daily dosing (large dose once a day gives your kidneys a break)
   A. Hartford Nomogram
   - 7mg/kg first dose (less if CrCl is <50ml/min 5mg/kg)
   - Assess level 6-14 hours after dose to eval Q24, 36, 48 hrs
   B. Large daily doses may be equally effective as smaller multiple daily dosing with lower toxicity
   C. Relying on POST-ANTIBIOTIC EFFECT
   D. Low serum concentrations allow the kidney cells to process drug and thereby reduce effects of accumulation

***NARROW THERAPEUTIC INDEX

Question 372

Identify medication

• Drug of choice - MRSA, osteomyelitis, skin and soft tissue infection
• Inhibit synthesis of peptidoglycan (complex with D-alannine precursor)
• Absorbed poorly ; oral no systemic side effects (stays in GI tract), IV don’t get into the gut but into tissues well (VRE hang out in the gut)
• Good for UTI at very high concentrations
• Adverse effects similar to AMINOGLYCOSIDES (Ototoxicity - peak, nephrotoxicity - through).
• **RED-MAN SYNDROME (histamine like reaction) - slow infusion down
• You can stop if you see that patient don’t have MRSA
• MRSA colonize in the nares while VRE colonize in the gut

Answer 372

VANCOMYCIN

**Doesn’t treat MRSA in the nares
MRSA - methicillin resistant staphylococcus aureus

Question 373

1. Identify MoA of vancomycin
   - inhibit biosynthesis of? How?
   - cidal or static?
   - PAE or no?

Answer 373

1. Vancomycin
   A. Inhibit the biosynthesis of peptidoglycan during cell wall formation
   - complexes with D-Alanyl-Dalanine precursor
   B. BACTERICIDAL for multiplying organisms
   C. Exhibits PAE (postantibiotic effect); after exposure to inhibitory concentrations of vancomycin, continued killing occurs (2 hrs)

**the drug also injures protoplasm by altering their cytoplasmic membranes

Question 374

1. Identify pharmacokinetics of vancomycin

A. Absorption
- when do you use IV? Oral?

B. Distribution
- CSF? (Only with what?)
C. Excretion
- type of elimination?

D. Peak/trough
-Controversy

E. Half life

Answer 374

A. Absorption

• Poorly absorbed from GI tract
• IV only for SYSTEMIC INFECTIONS
• Oral route for CLOSTRIDIUM DIFFICILE (pill vs drink IV)

B. Distribution

• distributed freely into most body fluids and tissues
• distribution to CSF only with inflammation

C. Excretion
- excreted almost entirely unchanged via GLOMERULAR FILTRATION

D. Peak/trough
- controversial discussions for higher trough range for certain indications (15-20 mcg/ml) ; Endocarditis, osteomyelitis, MENINGITIDIS

E.

• Half life 6-12 hours
• dosing interval q8hrs, 12 hrs, 24hrs, 48hrs
• pulse dosing based on random levels (ESRD, CKD, severe AKI)

Question 375

Identify adverse effects of vancomycin (6)

• local reactions?
• histamine like reaction?
• hematology?
• hypersensitivity?
• when you use with AMG?
• high peaks

Answer 375

1. Local Reactions Thrombophlebitis
2. Red-Man Syndrome
   • Histamine-like reaction
3. Hematologic Reaction
   • Neutropenia
   • Eosinophilia
   • Thrombocytopenia
4. Hypersensitivity
   • Maculopapular RASH
5. Nephrotoxicity
   • More common with concomitant AMG or other nephrotoxic agents.
6. Ototoxicity
   • Correlates with HIGH PEAK

Question 376

Identify spectrum of activity of Vancomycin

Answer 376

GRAM POSITIVE ORGANISMS ONLY (few extras)

1. Staphylococcus aureus; including MRSA
2. Staphylococcus epidermidis; including MRSE
3. Streptococcus spp.
4. Enterococcus spp.

**Extra; Clostridium spp, bacillus anthracis, corynebacteria

Question 377

Identify indications for vancomycin

1. Beta lactam?
2. Organisms with Gram stain?
3. What side effect of all abx can it treat
4. Prophylaxis for?
5. Surgical prophylaxis

Answer 377

1. Serious infections caused by beta-lactam resistant gram positive organisms
   . Vanc may be less bactericidal than beta-lactam agents for beta-lactam susceptible staph spp.
2. Gram positive organisms (serious B-lactam allergy)
3. Clostridium difficile colitis
   - Non responsive to Metronidazole OR
   - recurrent C.diff (hyper virulent strain)
   - severe and potentially life threatening
4. Prophylaxis for MAJOR SURGICAL PROCEDURES involving implantation of prosthetic materials
   - cardiac and valvular procedures and total hip replacement
5. Surgical prophylaxis (LIFE THREATENING allergy to beta-lactam antibiotics)
6. Prophylaxis for ENDOCARDITIS in patients at high risk for endocarditis

Question 378

When should vancomycin be avoided ?

1. Surgery?
2. Empiric therapy?
3. Coagulase?
4. Continued empiric?
5. MRSA?
6. C-diff
7. Renal failure?

Answer 378

1. Routine surgical prophylaxis
2. Empiric therapy in febrile neutropenic patients, UNLESS: evidence of possible gram positive infection (inflamed catheter site), hypotension, FQN prophylaxis, Severe mucositis, MRSA/PCN Resistant Strep Pneumo infections are prevalent
   in the hospital or patient has recent history of these infections
3. Coagulase negative Staph. in one blood culture (contamination)
4. Continued empiric use in patients whose cultures are negative.
5. Eradication of MRSA colonization.
6. Primary treatment of Clostridium difficile colitis
7. Treatment of infections caused by beta-lactam-sensitive gram positive organisms in patients with renal failure (dosing convenience).

Question 379

IDENTIFY MEDICATION (2)

• Individually, both are static but become CIDAL when put together
• Requires PICC or CENTRAL LINE (only available as IV option)
• Coverage; MRSA, PCN-resistant strep pneumo, VRE (covers E.faecium, NOT GOOD AGAINST E. FAECALIS)
• Also covers; anaerobes and some gram negative pathogens (H. Flu)

**identify MoA of both and each

Answer 379

Quninupristin/Dalfopristin (Synercid)

MoA
• Irreversibly bind to the 50s bacterial ribosomal subunit
• Quinupristin inhibits chain formation resulting in early
termination
• Dalfopristin inhibits peptide elongation by interfering with
peptidyl transferase

Question 380

Identify medication

• Works on 23sRibosome (bind to 23S ribosomal RNA of 50S subunit)
• Can lead to SEROTONIN STORM If given with antidepressant (monoamine oxidase inhibitor - MAOI)
• *identify
• class
• MoA
• bioavailability
• COVERAGE
• Adverse effects
• DRUG INTERACTION

Answer 380

LINEZOLID (ZYVOX)

• Oxazolidinone class – unique class
• Mechanism: bind to 23S ribosomal RNA of 50S
subunit
• IV = PO (100% bioavailable)

**Coverage; MRSA, VISA, VRE, PCN-resistant Strep pneumo

• Adverse effect
- Myelosupression: Thrombocytopenia (>2 weeks more likely)
- Superinfection (Yeast)
- Mitochondrial Toxicity (long courses) –?peripheral or optic
neuropathy

• Drug-Drug Interaction: MonoAmine Oxidase Inhibitor
watch co-administration with SSRI for serotonin storm
(Limit tyramine foods to <100mg/meal

Question 381

Identify medication

• MRSA colonization eradication from NARES

**application?
Other uses?

Answer 381

MUPIROCIN (BACTROBAN)

• Topical treatment (Cream/Ointment 2%)
• MRSA colonization eradication from Nares
• Controversial regarding long term efficacy of eradication
• Dose: 0.5 grams in each nostril BID x 5 days

• Other uses: Impetigo or infected wounds

Question 382

Identify medication

• Kitchen sink
• MULTIDRUG resistant of gram negatives (SPACE bugs)
• Comes as pro-drug format
• Same side effects as AMINOGLYCOSIDES and VANCOMYCIN - Ototoxicity and nephrotoxicity

**what class ?
Static or cidal?
**when do you use it?

Answer 382

COLISTIN

• polymyxins E (colistin)
• bactericidal

**Reserved for last ditch efforts
• Pan-resistant gram negative organisms
• Often times Pseudomonas and Acinetobacter (SPACE)
• Resistant PEK bugs

Question 383

Identify antibiotic

• GOOD FOR UTI cause you don’t get high concentratiosn in other places
• If you have lots of drug allergies and can’t tolerate anything else use this drug**
• *
• derivative of? Cidal or static?
• coverage?
• adverse effect?

Answer 383

FOSFOMYCIN (Monrol)

• PHOSPHORIC ACID derivative; BACTERIOCIDAL
• UTIs only (low serum concentrations)
• Multiple antibiotic allergy patient

• MDR pathogens

• Gram positive and gram negative organisms
• MRSA/VRE (Vancomycin resistant enterococcus)
• ESBL

• ADR: Mostly GI TOLERANCE in nature

Question 384

Identify antibiotics

• Very expensive
• Community acquired pneumonia
• Difficult gram negative

Unique coverage;
- MRSA/VRE, Gram negative bacteria (Carbapenem resistant Enterobacteria=CRE), Acinetobacter (not Pseudomonas), Anaerobes (GI infections)

IDENTIFY

• static or cidal?
• use?

Answer 384

TIGECYCLINE (Tygacil)

• GLYCYLCYCLINE agent– BACTERIOSTATIC
• Complicated skin infections • Complicated intra-abdominal infections • Community Acquired pneumonia (CAP)

**DOES NOT attain high serum concentrations

Question 385

Identify antibiotics

• Very popular and commonly used at home
• Used for Gram positive - MRSA and VRE. Taking the place of vancomycin
• Less nephrotoxicity or red man syndrome seen with vancomycin
• **S.E RHABDOMYOLYSIS (when used in combination with statins). Check CPK levels at baseline and weekly.

Identify

• static or cidal?
• coverage?
• use?
• does not cover? WHY?**
• 2 adverse effects

Answer 385

Daptomycin (cubicin)

• LIPOPEPTIDE (BACTERIALCIDAL)
• Covers GRAM POSITIVE organsims very well
• MRSA (MIC>2 Vanc) and VRE
• Complicated skin and soft tissue infections
• 4mg/kg daily (requires renal adjustment)
• Staph aureus and MRSA bacteremia/Right sided Endocarditis
• 6mg/kg daily (requires renal adjustment)
• DOES NOT cover Pneumonia
• INACTIVATED by PULMONARY SURFACTANT
• ADR:
• Rhabdomyolysis
• Eosinophilic pneumonia (RARE)

Question 386

IDENTIFY antibiotic

• Derivative of vancomycin
• Potential of nephrotoxicity and red man syndrome with infusion
• Can prolong QT interval
• Only benefit is you dont check levels at much?
• Prefer vancomycin to this drug **
• *identify
• class
• coverage?
• adverse effects?

Answer 386

Telavancin (Vibativ)

• GLYCOLIPOPEPTIDE
• Coverage; Gram POSITIVE organisms (SSI); staph (including MRSA), strep and enterococcus

- Adverse effects 
• Nephrotoxicity
• Red man syndrome with infusion
• QT prolongation
• Pancreatitis (*rare)

Question 387

How do you pick abx that covers SPACE bugs 🕷

• cell wall inhibitors
• DNA gyrase
• 30S subunit

Answer 387

1. Pick one of the cell wall inhibitors (top row)
   - PCN (piperacillin/zosyn, ticarcillin/timentin- dont use in CHF patient)
   - Cephalosporin (ceftaz, cefepime); both cover PSEUDOMONAS
   - Carbapenems (DIME - cause seizures)
   * *If you have PCN anaphylaxis allergy, use Aztreonam
2. Combined with one of the two below for different MoA
   - DNA gyrase = FQN (ciprofloxacin, levofloxacin)
   - 30 S = AMINOGLYCOSIDES (gentamycin, tobramycin, amikacin)

Question 388

Summarize the 6 classes of PCN covered

**PAACUB

*****Most common side effect to continuous PCN use

Answer 388

• *PAACUB
  1. Pen V and Pen G

2. Antistaphylococcal (methacillin, Nafcillin, Ox, Cloxacillin, Dicloxacillin) ; treat strep and staph
3. AminoPCN (ampicillin, Amoxicillin); enterococcus
4. CarboxyPCN (ticarcillin); don’t use in CHF patients
5. UreidoPCN (piperacillin)
6. Beta-lactamase inhibitors COMBOS; (clauvulanate, sulbactam, tazobactam)
   - Unasyn, augmenting, timentin, zosyn

Question 389

Summary; identify classes

1. Cover gram negatives with nephrotoxicity and ototoxicity
2. Cover gram positives with nephrotoxicity and ototoxicity
3. Cover gam positives (resistance) and cause Serotonin storm with MAOI antidepressant
4. MRSA colonization in nares
5. UTI only (2)
6. Gram positive (resistance). Gets inactivated by lung surfactant so does not treat pneumonia
7. Derivative of vancomycin
8. Does not treat bacteremia

Answer 389

1. Aminoglycosides
2. Vancomycin
3. Linezolid
4. Mupirocin
5. Fosfomycin (and nitrofurantoin)
6. Daptomycin
7. Telavancin
8. Tigecycline

Question 390

Identify medication

• Bacteria must synthesize folic acid from PABA
• Sulfonamides is considered BACTERIOSTATIC
• Usually combined with TRIMETHOPRIM and known as BACTRIUM
• Used in UTIs and everything - GOOD GRAM NEGATIVE COVERAGE

**identify 
Adverse effects (4 major)

Answer 390

SULFONAMIDES

S.E
• Nephrotoxicity and CRYSTALLURIA - (hydration will treat crystal urea)
• Steven Johnson Syndrome
• Dont give in 3rd trimester - KERNICTERUS (compete for bilirubin binding on albumin

Question 391

Sulfonamides - structure and chemistry

• similar in structure to what precursor?
• why do you need this precursor?

Answer 391

a. All sulfonamides are similar in structure to PABA (para-aminobenzoic acid)

B. PABA is a precursor required by bacteria for FOLIC ACID SYNTHESIS

Question 392

Sulfonamides - MoA

1. Bacteria require what acid which is a derivation of folic acid.
   * *This is a cofactors for synthesis of what? (3)
2. Bacterial cell wall are impermeable to 🤷‍♀️?
   - sulfa compete with PABA for what enzyme?
   - which has increased affinity for the enzyme?
3. Why are host cells not affected?
4. Static or cidal?

Answer 392

1. Bacteria require tetrahydrofolic acid (derivative of folic acid)
   - Cofactor in the synthesis of thymidine, purines, and ultimately DNA.
2. Bacterial cell walls are impermeable to FOLIC ACID
   - Bacteria must synthesize it from PABA
   - Sulfonamides compete with PABA for the enzyme DIHYDROPTEROATE SYNTHETASE
   - SULFONAMIDES may have an increased affinity for the
   enzyme than the natural substrate, PABA.
3. Host cells are not affected due to the fact that they
   require preformed folic acid; they CANNOT SYNTHESIZE FOLIC
   ACID.
4. BACTERIOSTATIC

Question 393

Summary folic acid pathway (PFTA)

• *identify the 2 enzymes
• what 2 abx compete with the enzymes

Answer 393

PABA - Folic acid - Tetrahydrofolic acid - AA

• PABA - folic acid (Dihydropteroate synthetase)
• Folic acid - Tetrahydrofolic acid (dihydrofolate reductase)

1. SULFONAMIDES; compete with dihydropteroate synthetase (PABA - folic acid)
2. TRIMETHOPRIM; compete with dihydrofolate reductase (Folic acid to THF acid)

Question 394

SULFA

1. Identify excretion of sulfa (most use?)
2. Adverse reactions (6)

Answer 394

1. Excretion
   - renal; via glomerular filtration
   - the extent of glomerular filtration varies with each agent
   - commonly used for UTIs
2. Adverse reactions
   A. Anaphylaxis

B. Cutaneous reactions

• morbilliform rash
• Steven Johnson syndrome ***
• Erythema multiforme
• photosensitivity rash

C. Hematologic reactions

D. Hypersensitivity reactions
- Drug, fever, rash

E. Nephrotoxicity

• CRYSTALLURIA with less soluble compounds (sulfadiazine and sulfathiazole)
• administer with FLUIDS - check hydration status of patients prior to use

F. KERNICTERUS

• when given in last months of pregnancy (3rd trimester)
• compete for bilirubin binding sites on plasma albumin
• results in increased fetal blood levels of unconjugated bilirubin

Question 395

1. Identify coverage of sulfonamides
2. Mechanism of resistance
3. Indications of use

Answer 395

1. Coverage (good gram negative + staph and strep)
   A. Gram positive; staph (MRSA), strep, bacillus antracis
   B. Gram negative; piddly, PEK, CE)
   **others; chlamydia (atypical), Protozoa- malaria, norcardia
2. • overproduction of PABA (neisseria, staph)

Question 396

IDENTIFY medication

• It is bacteriostatic but if combined with sulfa become bactericidal (Bactrium)
• Be cautious with patient with FOLATE DEFICIENCY; pregnant woman, alcoholic
• Similar coverage to sulfa; UTI, STDs
• Can use for traveler’s diarrhea (prefer FLUOROQUINOLONES for this tho)

Answer 396

TRIMETHOPRIM

• BACTRIUM - drug of choice for Stenotrophomonas maltophilia (DOC)

Question 397

1. Identify MoA of trimethoprim

• inhibits what enzyme?
• what changes depending on growth conditions

2. Excretion of trimethoprim

Answer 397

1. A.
   - Non-sulfonamide pyrimidine analogue
   - INHIBIT DIHYDROFOLATE REDUCTASE which prevents the formation of THF acid

B. Approx 50,000 times more active against bacterial dihydrofolate reductase than the human enzyme

C. Bacteriostatic or bactericidal depending on the growth conditions

2. Excretion
   - Renal; excreted 80% unchanged via glomerular filtration and tubular secretion

Question 398

1. Identify adverse effects of TRIMETHOPRIM (4)
2. Spectrum of activity
3. Indications/use

Answer 398

1. Adverse effects 
A. Cutaneous reactions 
- pruritis 
- rash 
B. GI reactions 
- N/V/D 
- elevated serum transaminases, bilirubin 
C. Hematologic reactions 
D. Caution in patients with possible FOLATE DEFICIENCY 
- alcoholics 
- pregnant women 
- debilitated patients 
- malabsorptive syndromes 

2. Spectrum ; used in conjunction with dapsone (intolerant to sulfa/tmp.)
   A. Gram positive; staph and strep, bacillus
   B. Gram negative; piddly, PEK, CE
   C. Other; Pneumocystis carinii**
3. Indications
   - Acute uncomplicated UTI
   - recurrent UTI prophylaxis *
   - traveler’s diarrhea *(tx and prophylaxis)

Question 399

BACTRIUM (combination of what 2 drugs)

1. MoA
   - synergy or antagonist?
   - static or cidal?
   - what is the goal?

Answer 399

BACTIUM - trimethoprim/sulfamethoxazole

• Combined mechanisms of both agents (SYNERGISTIC).
• Combination is usually BACTERICIDAL
• Goal is to REDUCE the rate of emergence of RESISTANCE
• Pharmacokinetics, Adverse Effects, and Resistance are the same as with each component

Question 400

1. Identify spectrum of activity of Bactrium?
2. Identify indications/use of Bactrium (5)
   * *one major one
3. Drug interactions (2)

Answer 400

1. Spectrum
   - gram positive (staph and strep)
   - good gram negative coverage (piddly, PEK, CE)
   - other weird bugs (Protozoa malaria, pneumocystis carinii, chlamydia)
2. Indications/Use
   A. UTI; uncomplicated UTI, UTI prophylaxis, acute and chronic prostatitis
   B. RTI; COPD exacerbations, pneumonia, acute otitis media, acute sinusitis, PCP
   C. GI infections; salmonella/shigella, traveler’s diarrhea, cholera
   D. STDs; uncomplicated gonococcal infections, chancroid, bacterial vaginosis
   E. Other infections; STENOTROPHOMONAS MALTOPHILIA (DOC)
3. Drug interactions
   A. Warfarin; highly likely to POTENTIATION ANTICOAGULANT effects
   B. Methotrexate; sulfa can displace MTX from protein binding sites. INCREASE FREE METHOTREXATE

Question 401

Identify medication

• Like fofsmomycin in that it ONLY COVERS UTIs
• Increased risk of side effects
• S.E;

**side effect (4)

**what reasons give you eosinophilia

Answer 401

NITROFURANTOIN

Side effects

1. PERIPHERAL NEUROPATHY in renal dysfunction patients
2. PNEUMONIA (lungs) like side effects
3. Does not get good enough tissue penetration - don’t like to use in males. Don’t have high enough concentration to reach kidneys (only UTI)
4. HYPERSENSITIVITY (eosinophilia - NAACP - allergic drug reaction of parasites)

• NAACP; Neoplasm, asthma, allergic reaction to drugs, connective tissue, parasites. All reasons for Eosinophilia

Question 402

Nitrofurantoin

1. MoA
2. Pharmacokinetics
   - distribution (what conc are insignificant? Very high conc?)
   - excretion (effect of impaired GFR)

Answer 402

1. MoA
   - UNCLEAR mechanism of action
   - possibly interferes with the early stages of bacterial carbohydrate metabolism by inhibiting acetyl coenzyme A
   - possibly due to production of reactive 5-nitro anion, free radicals
2. Pharmacokinetics
   A. Distribution
   - serum/tissue concentrations are insignificant
   - Urine concentrations are very high

B. Excretion

• rate of excretion is linear, related to CrCl
• Patients with impaired GFR (decrease in efficacy, increase in systemic TOXICITY, do not use if CrCl <40-60 ml/min)

Question 403

Nitrofurantoin

1. Adverse effects (5)
2. ***Pulmonary adverse effects
   Acute vs subacute vs chronic
   - can they be reversible?
3. Spectrum
4. Indications (2)

Answer 403

1. Adverse effects
   A. Hypersensitivity reactions; rash
   B. Hematologic reactions; hemolytic anemia
   C. Hepatotoxicity
   D. Peripheral neuropathy; esp in renal insufficiency
   E. GI reactions; N/V/D, less with microcrystalline prep compared to microcrystalline suspension form
2. Pulmonary adverse effects (acute, subacute, chronic)
   A. Acute reaction - hypersensitivity
   - fever, cough, dyspnea, eosinophilia, infiltrate
   B. Subacute reaction - after 1 month of therapy
   - cough, dyspnea, interstitial infiltrate
   C. Chronic reaction - after 6 months of therapy
   - cough, dyspnea, interstitial infiltrate
   ** Subacute/Chronic Reactions are often reversible after the drug is stopped. However, can be irreversible/fatal.**
3. Spectrum
   Gram positive; staph, strep, enterococcus
   Gram negative; E.coli, klebsiella, CE
   **Resistance does not develop readily to nitrofurantoin
4. Indications
   - acute uncomplicated UTI treatment
   - UTI prophylaxis

Question 404

Identify medication

• Need acidic environment to switch to formaldehyde
• Only used for UTI prophylaxis, not recommended for acute UTI

Answer 404

METHENAMINE

Question 405

METHENAMINE

1. MoA
   - how do they kill bacteria?
2. Pharmacokinetics
   - absorption (bioavailability? Gastric acid effect? )
   - excretion

Answer 405

1. MoA
   - No antibacterial effect alone
   - At adequate urine pH (<5.5), it is hydrolyzed to FORMALDEHYDE which kills bacteria by DENATURING PROTEINS

2. Pharmacokinetics 
A. Absorption 
- rapidly absorbed from the GI tract 
- excellent bioavailability 
-

Question 406

METHENAMINE

1. Adverse effects
2. Spectrum
3. Indications

Answer 406

1. Adverse effects
   A. Hypersensitivity reactions
   - rash/pruritis
   - HIPPURATE form contains the dye TARTRAZINE; may lead to allergic reactions in asthma pts
   B. Hemorrhagic cystitis
   C. GI reactions; N/V/D
   **Avoid in Hepatic insufficiency; ammonia byproduct
   **Renal failure; acid forms could potentially lead to systemic acidosis
2. Spectrum
   - virtually all bacteria and fungi are susceptible to formaldehyde
   - certain urease positive bacteria (proteus) can alkalinity the urine (stops the conversion to formaldehyde)
3. Indications
   - UTI prophylaxis only
   - NOT recommended for tx of acute UTIs

Question 407

Methenamine

Factors affecting formaldehyde concentrations
**Methenamine concentrations in urine is affected by?;

Answer 407

1. Rate of hydrolysis of methenamine to formaldehyde
2. Rate of urine loss from bladder by voiding or drainage

** PEARL: *Frequent voiding of bladder (indwelling catheters or
intermittent cath) will decrease effects by removing
formaldehyde and by reducing the time of exposure of bladder
bacteria to formaldehyde.

Question 408

MACROLIDES

1. 3 types. Structure and chemistry
2. MoA
   - reversible binds to what ribosome? Goal?
   - static or cidal?
   - Mechanism of resistance?

Answer 408

Macrolides
1.
A. Erythromycin
B. Clarithromycin; 6-methoxy-erythromycin
C. Azithromycin; Nitrogen group added to the 14-member macrolide ring

2. MoA
   • Reversibly binds to the 50S-ribosomal subunit of
   bacteria; DECREASE PROTEIN SYNTHESIS

• Bacteriostatic
• Mechanisms of Resistance (because we use it too often)
• Decreased permeability of the cell envelope
• Alteration in 50S ribosomal receptor site
• Enzymatic inactivation of erythromycin by esterases.

Question 409

Identify the macrolide

• stimulates motilin? Use in diabetic patients with gastrocolitis?
• most prolonged QT interval
• side effects?

Coverage

Answer 409

• Erythromycin STIMULATES MOTILIN; useful in diabetic with gastroenteritis and cause the MOST PROLONGED QT INTERVAL
• GI intolerance on normal patients; irritates stomach wall. Cause nausea, vomiting and diarrhea
• CHOLESTATIC HEPATITIS; overall rare but more COMMON IN PREGNANT PATIENTS
• Large doses cause OTOTOXICITY and prolonged QT interval

**Family of MACROLIDES - covers staph, strep and ATYPICALS

Question 410

Macrolides

1. absorption (erythromycin)
   - rapidly inactivated by?
   - what is absorbed better in fasting state?
   - what is not affected by food?
2. Distribution (all 3)

Answer 410

1. ERYTHROMYCIN absorption
   • Erythromycin base
   - Rapidly inactivated by GASTRIC ACID; Enteric coated and film coated forms to decrease this inactivation

• Base, stearate, and ethylsuccinate

• Absorbed better in fasting state
• Will the patient tolerate on empty stomach?

• Emycin Estolate
- Not affected by food

2. Distribution
   • Distributes in tissues longer than in blood.
   • Very high concentrations in alveolar macrophages and leukocytes compared to extracellular fluids.
   • Azithromycin tissue concentrations (LONG HALF LIFE)
   - 10-100 X serum concentrations
   - Allows for 5 day course of therapy

Question 411

IDENTIFY metabolism/excretion of macrolides

• excretion form?
• metabolized where?

Answer 411

1. Erythromycin
   - mainly BILIARY EXCRETION
   - small percent in urine
   - large portion of absorbed drug can be inactivated in LIVER BY DEMETHYLATION
2. Clarithromycin
   - metabolized in liver by oxidation and hydrolysis
   - 20-30% of drug excreted into the urine unchanged
3. Azithromycin
   - small proportion is metabolized
   - biliary excretion mainly
   - half life is 68 hours (after multiple doses)
   * *consistent with a slow release of drug from tissues
   * *aids in allowing 5 day regimen

Question 412

Adverse effects of macrolides

1. Erythromycin
2. Clarithromycin/azithromycin

**which has more severe GI effects? Most prolonged QT?
Which should be avoided in pregnancy? (Which form?)

Answer 412

1. Erythromycin
   - GI; abdominal cramps, N/V/D
   - thrombophlebitis; associated with IV administration
   - allergic reactions
   - CHOLESTATIC HEPATITIS; overall rare. AVOID ESTOLATE FORM IN PREGNANCY. N/V, abdominal pain followed by jaundice, fever, LFT changes, Hypersensitivity rxn to the Estolate compound
   - large IV doses; ototoxicity, QT prolongation
2. Clarithromycin/Azithromycin
   - GI; not as severe as erythromycin
   - HA
   - dizziness
   - allergic reactions

Question 413

Macrolides - drug interactions

A. Metabolites from inactive complexes with p450 enzymes (2)
** decreased metabolism of?

B. Does not appear to inactivate p450 enzymes (1)

Answer 413

1. Erythromycin/clarithromycin
   - metabolites form inactive complexes with p450 enzymes
   - decreased metabolism of; Theophylline, Warfarin, Carbamazepine, Cyclosporine
2. Azithromycin (better GI tolerance)
   - does not appear to inactivate p450 enzymes

Question 414

Identify spectrum of activity of macrolides (5)

• which has better coverage ? (2)

Answer 414

1. Gram positive organism (staph and strep)
2. Atypicals
3. Clarithromycin/azithromycin
   - H.flu, M.cat (THE BIG DIFFERENCE) ?
4. MAC 🖥
   - clarithromycin and azithromycin (both have better coverage)
5. Helicobacter pylori (associated with peptic ulcers)
   - clarithromycin
   - prevpak

Question 415

Indications/uses of macrolides (6)

• *Big one (not common in others)
• *main side effect to watch for?

Answer 415

ATYPICALS - watch for prolonged QT interval

1. PCN allergic patients
2. CAP - community acquired pneumonia (clarithromycin and azithromycin)
3. Mycoplasma pneumonia
4. Legionnaire’s disease
5. Chlamydia trachomatis nongonococcal urethritis and cervicitis
6. Chlamydia trachomatis during pregnancy (BUT NOT THE ESTOLATE FORM)

Question 416

Identify medication

• High bone penetration (does not need renal adjustment)
• Does not cover atypical
• Covers staph and strep and anaerobes and MRSA 50% of time
• S.E; diarrhea, C-diff (pseudomembranous colitis), hepatotoxicity (mild and severe)
• Use in PCN allergy patient

Answer 416

CLINDAMYCIN

Question 417

Clindamycin

1. Structure
   A. Derived from?
   B. MoA (similar to?)
2. Pharmacokinetics
   - bioavailability
   - target?
   - metabolized
3. Spectrum (4)
4. Adverse effects (4)

Answer 417

1. Structure and MoA
   A. Derived from LINCOMYCIN ; chemical modification allowed it to be more potent and better absorption
   B. MoA; binding of 50S ribosome leading to inhibition of protein synthesis **similar to macrolides?
2. A. Bioavailability 90%; food delays absorption but not extent
   B. Good tissue penetration; skin and soft tissue infections
   C. Metabolized by the liver
3. Spectrum
   - streptococcus
   - staphylococcus; limited bactericidal rate compared to beta lactams
   - ANAEROBES; peptostreptococcus, bacteroides, clostridium
   - toxoplasmosis (sulfa allergy)
4. Adverse effect
   - allergic reactions
   - diarrhea 20% of patients ; more common with ORAL form
   - clostridium difficile (pseudomembranous colitis)
   - Hepatotoxicity (mild and severe)

Question 418

Identify medication

• Last ditch effort due to hallmark side effects
• Excellent CSF penetration (cross BBB) - use in meningococcal infections
• Broad coverage; gram positive, gram negative, aerobic and anaerobic, rickettsia, chlamydia

**identify 2 MAJOR SIDE EFFECT

Answer 418

CHLORAMPHENICOL

1. Idiosyncratic APLASTIC ANEMIA; can’t stop this
2. GRAY BABY syndrome; abdominal distention , vomiting, cyanosis, circulatory collapse w/ conc above 50

Question 419

Chloramphenicol

1. MoA
2. Pharmacokinetics
3. Spectrum
4. Adverse effects
5. Indication/uses

Answer 419

1. MoA

Question 420

Chloramphenicol

1. Spectrum
2. Adverse effects
3. Indication/uses (2)

Answer 420

1. Spectrum (broad)
   - gram positive
   - gram negative
   - aerobic or anaerobes
   - rickettsia
   - chlamydia
2. Adverse effects
   A. Hematologic ; IDIOSYNCRATIC APLASTIC ANEMIA
   - anemia, leukopenia, thrombocytopenia
   - can lead to leukemia
   B. GRAY BABY SYNDROME
   - abdominal distention, vomiting, cyanosis, circulatory collapse
   - fundamental mechanism of toxicity involved inhibition of mitochondria protein synthesis
   - Newborns lack an effective glucuronic acid conjugation
   mechanism that degrades and detoxifies the system of
   Chloramphenicol in the urine
   - Drug accumulates →Toxicity →Vomiting, Flaccidity,
   HYPO-thermia, respiratory collapse, and GRAY COLOR
   - Generally associated with concentrations > 50mcg/ml
3. Indications/uses
4. BACTERIAL MENINGITIS
   - H.flu, strep pneumo, neisseria meningitidis
   - PCN/cephalosporin allergic
   - oral alternative when IV cannot be used
   S. Rickettsial Infections

Question 421

Identify 2 similarities in the effects of quinolones and tetracyclines

Answer 421

1. Both have age restriction
   A. Quinolones; only 18 y.o and above
   B. Tetracycline; only 8 y.o and above
2. Both get bound up by CATIONS (e.g calcium)

Question 422

1. Name 2 combo sets of drugs that follow concept of SYNERGY
2. Name 2 drugs that allow for PAE (post antibiotic effected)

Answer 422

1. Synergy
   A. Trimethoprim/sulfamethoxazole
   B. Penicillin/Aminoglycosides
2. PAE
   * Aminoglycosides and FLUOROQUINOLONES

Question 423

1. Identify 4 abx with beta lactam in their structure

2. Identify beta lactamase inhibitors and their coverage (4)

Answer 423

1. Beta lactam abx 
A. PCN 
B. Cephalosporins 
C. Carbapenems 
D. Monobactam (Aztreonam) 

2. Beta lactamase inhibitors (clauvulanate, sulbactam, tazobactam)
   - Unasyn (ampicillin/sulbactam)
   - Augmentin (Amoxicillin/clauvulanate)
   - Timentin (ticarcillin/clauvulanate)
   - Zosyn (Piperacillin/tazobactam)
   * *Add STAPH COVERAGE AND ANAEROBES
   * will help with organisms who produce beta lactamases

Question 424

Identify medication

• Prolongs QT interval
• CNS**
• Don’t use in kids under 18 years old (exception in cystic fibrosis kid) - result in RUPTURED TENDONS
• Double theophylline levels
• Bound up by antacids, iron, sucralfate, multivitamins
• Interfere with warfarin

Answer 424

Quinolones

Question 425

Identify MoA of quinolones

• target? How does it work?
• cidal or static?
• PAE?

Answer 425

1. Target; DNA gyrase (topoisomerase II)
   - DNA gyrase is essential for supercoiling of cellular DNA by a nicking, pass through, and resealing process
2. Quinolones inhibit bacterial DNA gyrase and topoisomerase IV
3. BACTERICIDAL
4. PAE (Postantibiotic Effect)
   - **after exposure to inhibitory concentrations of quinolones, CONTINUED KILLING OCCURS
   - the PAE average is approx 1-2 hrs
   - tends to increase with increasing concentrations and length of exposure

Question 426

1. Identify Adverse effects of quinolones (7)

Answer 426

1. Hypersensitivity rxn
   - Photosensitivity
2. Hematologic reactions
   - neutropenia
   - eosinophilia
3. Cardiac; QT prolongation
4. GI; diarrhea, N/V
5. Nephrotoxicity (rare)
   - interstitial nephritis
6. CNS**; headache, dizziness, mental status change
7. Musculoskeletal
   - ARTHROPATHY ; caution in <18 years
   - Tendon rupture; co admin with steroids, age >60

Question 427

Identify drug interactions of quinolones (3)

Answer 427

1. Theophylline
   - ciprofloxacin can double theophylline levels
   - levofloxacin; little to no effect
2. Antacids/Iron/sucralfate/Multivitamins
   - Do not give within 2-4 hours of quinolone dose
3. Warfarin
   - increased anticoagulant effect possible due to metabolism or protein binding changes
   - levofloxacin; possible no effect - still monitor

Question 428

Identify the spectrum of activity of quinolones
(4)

• *which does not cover pseudomonas
• *which has indication for complicated abdominal infections?

Answer 428

1. Gram positive
   * older agents (ciprofloxacin and ofloxacin) are not good gram positive coverage
   * newer agents appear to have better staph/strep coverage
   - levofloxacin, MOXIFLOXACIN, gemifloxacin
2. Gram negative
   - coverage varies among different agents (SACE vs SPACE)
   * Cipro and levofloxacin (SPACE)
   * Moxifloxacin (SACE)
3. Anaerobic coverage
   * newer agent only - MOXIFLOXACIN

Question 429

Identify quinolone type

A. Generally considered very good coverage
- wide range of FDA approved indications
B. Gram positive (generally considered poor)
- consider newer FQN for better coverage OR
- adding another agent with gram (+) coverage
C. Gram negative
- drug generally considered most potent of quinolones against gram negative organisms
- specifically most potent against PSEUDOMONAS
D. EXCELLENT BIOAVAILABILITY - use oral form if possible
- functioning GI tract required (do not use if ileum or SBO)

Answer 429

CIPROFLOXACIN (quinolones)

Question 430

Quinolones (levo, gemi, moxi)

1. Gram positive coverage
   - which cover staph and strep
2. Gram negative coverage
   - which has most potency
   - which do not treat pseudomonas (2)
3. Respiratory pathogen?
4. Bioavailability?

Answer 430

1. Gram positive coverage
   - all 3 are good for staph and strep
   - coverage includes excellent PCN resistant strep pneumo (common for CAP infections with previous Abx use, elderly or kids in day care)
2. Gram negative coverage
   - levofloxacin (SPACE) potency is less than Ciprofloxacin
   - No Pseudomonas for GEMIFLOXACIN OR MOXIFLOXACIN (SACE)
3. Atypical respiratory pathogens
4. Excellent bioavailability - use oral agent

Question 431

Quinolones continued

1. What is hybrid between cipro and newer agents
2. Which one - *complicated intra-abdominal infections
3. Which does not cover UTI
4. Mechanisms of resistance

Answer 431

1. LEXOFLOXACIN; is a hybrid between Ciprofloxacin and the newer agents gemifloxacin and moxifloxacin
2. MOXIFLOXACIN unique xters
   - Anaerobes (complicated intra abdominal infections)
3. MOXIFLOXACIN does NOT cover UTIs
   - poor urinary concentrations
4. Mechanism of resistance
   A. Altered target enzyme (altered DNA gyrase)
   B. Reduction of quinolone concentrations intracellularly
   - altered drug permeability across cell membrane due to changes in porin channels
   - Efflux of drug from bacterial cell

Question 432

Quinolones (place in therapy)

1. Indications/use (8)
2. A. Intra-abdominal infections
   B. Skin/skin structure infections (caused by susceptible organisms)
   C. Bone and joint infections caused by susceptible organisms

Answer 432

1. Indications
   - LRIs (good penetration)
   - CAP and HAP (pseudo risk)
   - Gonorrhea
   - Chlamydia
   - UTIs (Not moxifloxacin/gemifloxacin)
   - PID (pelvic inflammatory disease)
   - Prostatitis (28 days)
   - Gastroenteritis/ infectious diarrhea
2. A. Intra-abdominal infections; MOXIFLOXACIN or cipro/metronidazole or levo/metronidazole

B. Skin/skin structure infections;
- if you discover gram positive from tissue, cipro/ofloxacin don’t cover (+) well so add some extra stuff for gram (+) coverage; levo, gemi and moxi are better gram positive coverage. MOXIFLOXACIN covers anaerobes well

C. Bone and joint infections; similar to B. Not cipro/ofloxacin if Infection is gram positive

Question 433

1. Identify medication

• Coverage; staph, strep, piddly gram negatives, ATYPICALS (if you don’t have sulfonamides pick this drug - treat odd/weird infections)
• take 4 times a day (bad compliance)
• STATIC - but very efficacious
• Very few need renal adjustment

2. Identify adverse effects? (3)

Answer 433

1. TETRACYCLINES
2. ADVERSE EFFECTS
   A. Photosensitivity
   B. DISCOLORATION OF DEVELOPING TEETH AND PREGNANCY (don’t use in kids below 8 years old)
   C. Outdated tetracycline can cause fanconi-like syndrome

Question 434

1. Identify drug members of tetracyclines (6)
   - which is used in adolescents and acne? SIADH?
2. Identify MoA
   A. Binds to what?
   B. Static or cidal?
   C. What decrease absorption?

Answer 434

1. Members 
A. Doxycycline (Vibramycin)
B. Minocycline (Minocin, Vectrin) 
C. Demeclocycline (Declomycin); adolescents acne, SIADH
D. Oxytetracycline (Terramycin) 
E. Chlortetracycline (Aureomycin) 
F. Tetracycline (Achromycin, Panamycin) 

2. MoA
   A. Reversibly binds to 30S ribosomal subunit
   B. BACTERIOSTATIC
   C. FOOD decreases absorption; variable from 20 - 50% for various TCNs

Question 435

Tetracyclines

1. Give ways in which bioavailability varies dependent on products (2)
2. Elimination of tetracyclines (2)
   - divide the 5 members into the 2 elimination routes

Answer 435

1. Bioavailability varies dependent on products
   A. Doxy and Minocycline (90-100%)
   B. Tetracycline, demeclocycline, ocytetracycline (58-75%)
2. Primary elimination
   A. Renally (TOD); TETRACYCLINE, Oxytetracycline, Demeclocycline
   B. Hepatobiliary (DM); DOXYCYCLINE, Minocycline

Question 436

Tetracyclines

1. Adverse reactions (5)
2. Drug interactions
   - what chemicals/meds/drinks decrease absorption?
   - potential antagonism effect how?
   - effect on warfarin?

Answer 436

1. Adverse reactions
   A. Photosensitivity

B. DISCOLORATION of DEVELOPING TEETH; bones and teeth is developing during pregnancy and in children through 8 years old

C. Reversible DIABETES INSIPIDUS associated with DEMECLOCYCLINE; use this side effect to treat SIADH

D. VESTIBULAR side effects associated with Minocycline
- dizziness, ataxia, vertigo

E. Franconi-like Syndrome

• N/V, lethargy, polydipsia, polyuria, proteinuria, acidosis, hypokalemia
• associated with use of OUTDATED citric acid formulation of tetracycline

2. Drug interactions
   A. Decreased absorption of TCH agents when you co-administer via CHELATION
   - Di and Trivalent cations (Ca, magnesium, zinc, aluminum, iron)
   -

Question 437

Tetracyclines

1. Identify spectrum of activity
   - broad spectrum coverage of ? (4)
2. Clinical uses (5)
   Continued in next question

Answer 437

1. Spectrum; broad spectrum
A. Gram positive (staph, strep) 
B. Gram negative (H.flu, neisseria) 
C. Atypicals (CML) 
D. Rickettsia 

2. Clinical uses
   A. Rickettsia infections (parasites); Rocky Mountain spotted fever
   B. Mycoplasma pneumonia
   C. Chlamydia infections; urogenital 7 days of Doxy
   D. Acne
   E. H.pylori in combination w/ other agents
   - Bismuth, metro, PPI
   - QID dosing; less patient compliance

Question 438

Tetracyclines - clinical uses

1. Brucellosis (2 meds)
   - how do humans get it
   - S&S
2. Vibrio cholera/vulnificus
3. Borrelia Burgdorferi
4. Atypical clinical use
   - what specific medication?
5. Take home points

Answer 438

1. Brucellosis; from unpasteurized cheeses, milk (not common in US). Humans get infected by coming in contact with animals or animal products contaminated with brucella.
   - FLU LIKE SYMPTOMS; fever, sweats, headaches, back pains and physical weakness
   - severe infection of CNS or lining of the heart
2. Vibrio cholera; ACUTE DIARRHEA DISEASE, can lead to severe dehydration in hours
   - cause disease in those who eat contaminated seafood or have open wound that is exposed to seawater
3. Borrelia burgdorferi; LYME DISEASE (bacterial disease)
   - within 1-2 weeks; bull’s eye rash with fever 🤒, headache and muscle or joint pain. Some have flu like symptoms with no rash.
   - after days/weeks - bacteria spread and you get rash every ear, pain from joint to joint and signs of inflammation of heart and nerves
   - if left untreated; SWELLING and PAIN in major joints or mental chnages months after being infected
4. Atypical use; SIADH
   - DEMECLOCYCLINE only
5. Take home
   - Category X, also contradicted in kids < 8 years old
   - Photosensitivity
   - Fancoli like syndrome; outdated tetracycline
   - divalent and trivalent cations will chelate antibiotic (calcium, magnesium, aluminu, diary)
   - treatment of SIADH (demeclocycline)

Question 439

1. Identify family of organisms

• Obligate intracellular pathogens
• Considered a virus for a very long time - cause they are intracellular and small size
• NO PEPTIDOGLYCAN layer; cell wall structure not as rigid as a typical Gram negative bacteria
• They have are sensitive to beta lactamase (beta lactam penicillins can’t work)

2. Identify 3 species
3. Why were they reclassified to bacteria
   - similarity to gram negative? Nucleic acid? Ribosomes? Abx?

Answer 439

1. CHLAMYDIACEAE family
2. 2 genera; 3 species - trachomatis, pneumoniae, psittaci
   A. Chlamydia; C. Trachomatis
   B. Chlamydophilia; C. Pneumoniae and C. Psittaci
3. Reclassified to bacteria
   - posses inner and outer membrane similar to gram negative (but lack peptidoglycan layer)
   - contain but DNA and RNA
   - has prokaryotes

Question 440

1. Chlamydia has a unique developmental cycle in that it exists in 2 forms. Identify
   A. Extracellular (not active but infectious). Enter cell wall via endocytosis
   B. Intracellular. Active form but non-infectious
2. Describe the developmental cycle (4 steps)
3. Can chlamydia synthesize ATP? Where does it get ATP to use?

Answer 440

1. Chlamydia (2 forms
   A. ELEMENTARY BODIES; inactive infectious forms
   B. RETICULATE BODIES; metabolically ACTIVE non-infectious forms
2. I. EBs infect host cell and converts to RBs
   II. RBs replicate using

Question 441

Chlamydia trachomatis

1. Identify the 2 biovars and further differentiation
2. What is an important structural component
3. What causes for 18 serologic variants
4. Identify serovars of trachoma (like pink eye); (4)
5. Serovas of urogenital disease
6. Serovas of LGV (5)

Answer 441

1. Clamydia trachomatis - 2 biovars - trachoma and LGV
   A. Trachoma; Trachoma and Urogenital tract disease
   I. Trachoma; Serovars A, B, Ba, C
   II. Urogenital disease; Serovars D-K
   B. LGV (lymphogranuloma venereum); Serovars L1, L2, L2a, L2b, L3
2. Important structural components - MOMP (major outer membrane protein)
3. VARIABLE REGIONS in gene encoding MOMP results in 18
   serologic variants or Serovars
4. Trachoma: serovars A, B, Ba, C
5. Urogenital tract disease: serovars D-K
6. Lymphogranuloma venereum: L1,L2, L2a, L2b, L3

Question 442

CHLAMYDIA TRACHOMATIS - pathogenesis and immunity

1. • are they a lot or limited EBs that infect?
   • where are EB receptors restricted to? Found?
   • is trachoma or LGV more invasive? Why?

2.

Answer 442

1. • LIMITED range of cells that can infect
   • EBs receptors are restricted to nonciliated columnar, cuboidal and transitional epithelial cells
   • found on mucous membranes of; urethra, endocervix, endometrium, Fallopian tubes, anorectal, respiratory tract, conjunctivae
   • LGV serovars MORE INVASIVE due to replication within mononuclear phagocytes (macrophage - host cell is a macrophage so more virulent)

Question 443

Epidemiology of Chlamydia trachoma (A, B, Ba, C)

1. Leading cause of?
2. WHO estimates
3. Endemic areas
4. Infections in what age group
5. ***tramission (how?) - What body part

Answer 443

1. Leading cause of PREVENTABLE BLINDNESS worldwide
2. WHO estimates
   ◦ 6 million blind due to trachoma
   ◦ 150 million in need of treatment
3. Endemic in North and sub-Sahara Africa, Middle East,
   Asia, and South America
4. Infections predominantly in CHILDREN and are chief
   reservoir for endemic disease
5. Transmitted EYE to EYE via droplet, hand, clothing, and
   eye seeking flies

Question 444

1. Identify disease

▶ Most common bacterial STI in US
▶ 2006 reported 1million infections
▶ Underestimate-many patients do not seek medical
care, ASYMPTOMATIC DISEASE
▶ Estimated 2.8 million new infections each year in US
▶ 50 million new infections each year worldwide

2. Identify 2 epithelium types
   - which condition are you born with that make you more susceptibe to chlamydia infections?

Answer 444

1. Urogenital disease (C. Trachoma serovars D - K)

**more common in women than men

2. A. Transition zone; columnar to squamous epithelium ]

B. CERVICAL ECTROPIAN; visible columnar epithelium
• Born with the condition
• Visible columnar epithelial cells so EB can enter - more susceptible to chlamydia infections

Question 445

Identify condition \

• LYMPHOID GRANULOMA; more common in men and HIV patient
  ▶ Occurs only sporadically in US
  ▶ Highly prevalent in Africa Asia and South America
  ▶ Seen more frequently in men (women with more
  asymptomatic disease)
  ▶ Recent outbreaks reported in Europe and North
  America in MSM
  ▶ HIV co-infection common

Answer 445

LGV - Lymphogranuloma Venereum (L1, L2, L2a, L2b, L3)

**under chlamydia trachomatis

Question 446

Identify 2 phases of infection of chlamydia TRACHOMA

1. • Initial infection causes MILD self limited follicular conjunctivitis
   • Characteristic follicle on superior tarsal conjunctiva
   • Often asymptomatic
2. • Severity and duration of active trachoma predicts progression
   • repeated episodes infection lead to conjunctiva inflammation and eyelid scarring - entropian and triciasis (eyelashes going inward) - corneal abrasion and scarring and BLINDNESS

Answer 446

1. Active trachoma
2. Cicatricial disease
   - severe active trachoma - conjunctiva inflammation and eyelid scarring - entropian and trichiasis (eyelash going inward) - corneal abrasion and scarring and blindness

Question 447

Chlamydia Trachoma

1. When does trichiasis occur (eyelashes going inward)
2. What is the growth of vascular tissues over cornea called?
3. Evidence?

Answer 447

1. TRICHIASIS; occur when eyelid conjunctiva scar tissue contracts, distorting the lid margin and causing the eyelashes to rub on the cornea
2. PANNUS
   - growth of vascular tissue over the cornea as a result of edema and ulceration due to eyelash abrasion on the cornea
3. Evidence of corneal opacity blurring part of the pupil margin

Question 448

Identify condition

• Common in the US
• CERVICITIS is most common in women - inflammation of the cervix (soluble mediators of inflammation); PURULENT DISCHARGE - cervix try to heal then you have SCAR FORMATION - become infertile
• UTI like symptoms (urethritis) accompany cervicities

**Identify the different manifestations? (6)

Answer 448

UROGENITAL DISEASE in WOMEN (**from chlamydia trachoma K-D)

▶ Asymptomatic disease common in women (up to 80%)
▶ Clinical manifestations in women include bartholinitis,
cervicitis, endometritis, perihepatitis, salpingitis, and
urethritis
▶ Cervicitis most common presentation in women
▶ Mucopurulent discharge, friable cervix, and cervical edema
seen
▶ Urethritis often accompanies cervicitis and presents with
UTI like symptoms
▶ Fitzhugh-curtis syndrome: perihepatitis with inflammation
of liver capsule
▶ If untreated may develop PID

Question 449

Identify condition

▶ Most infections (75%) in men symptomatic
▶ Urethral discharge and/or dysuria
▶ Causes 35-50% of cases of NGU (non-gonococcal
urethritis)
▶ Incubation period longer than N. gonorrhoeae so
consider diagnosis in patients treated for GC who
present with new symptoms

Answer 449

UROGENITAL DISEASE in MEN (**In chlamydia trachoma K-D)

Question 450

Identify the following occulogenital syndromes caused by chlamydia trachoma

1. ◦ Acquired during passage of infant through infected birth canal
   ◦ Develops in 25% of infants whose mothers have active genital
   infections
   ◦ After incubation of 5-12 days develop swollen eyelids, hyperemia
   and purulent discharge
2. ◦ Afflicts 18-30 year olds
   ◦ Genital infection precedes eye involvement
   ◦ Transmitted via autoinoculation or oral-genital contact
   ◦ Mucopurulent discharge, keratitis, corneal infiltrates and scarring

Answer 450

1. Newborn inclusion conjunctivitis

2. Adult inclusion conjunctivitis

Question 451

Identify 2 other clinical disease caused by chlamydia trachomatis

1. ◦ Urethritis, conjunctivitis, polyarthritis, and mucocutaneous
   lesions
   ◦ Initiated by genital infection with C. trachomatis
   ◦ Typically occurs in young men
2. ◦ Occurs 2-3 weeks after birth
   ◦ Rhinitis initially then staccato cough and tachypnea
   ◦ Typically afebrile
   ◦ Chest x-ray shows bilateral interstitial infiltrates

Answer 451

1. REITER SYNDROME (autoimmune disease)

2. Infant pneumonia

Question 452

Identify clinical syndrome of Chlamydia

1. • NON PAINFUL LESIONS that may be accompanied by systemic symptoms
   • primary lesion (papule or ulcer) at site of infection develops after incubation period of 1-4 weeks
   • second stage of infection with inflammation and swelling of lymph nodes that drain the site of initial infection
   • *What can this lead to?
2. ◦ Caused by LGV serotypes (L1, L2, L2a, L2b, L3)
   ◦ Conjunctival inflammation with preauricular, submandibular,
   and cervical lymphadenopathy
3. become painful, fluctuant buboes that can rupture? Cause?

Answer 452

1. LGV - Lymphogranuloma venereum (from chlamydia trachomatis)
   ▶ Inguinal nodes most commonly involved – become painful, fluctuant buboes that can rupture
   ▶ PROCTITIS common in WOMEN with LGV due to lymphatic spread from cervix or vagina
   ▶ Untreated may resolve or become chronic with fistulas,
   strictures, and genital elephantiasis
2. Parinaud OCCULOGLANDULAR syndrome (eye infection)
3. LGV Inguinal nodes
   • Enlarged lymph nodes from lots of T cell proliferation
   • LGV - target macrophages but enter epithelial cell

Question 453

Identify laboratory diagnosis of chlamydia

1. • is symptomatic type easier to diagnose?

2.

• can you culture pus?
• what can you not culture? (2) why?

3. what can you culture (5)
4. why do cytology
5. cultured in cell culture vs nucleic acid based test

Answer 453

1. Symptomatic is EASIER to diagnose than asymptomatic
2. DO NOT culture PUS and VAGINA
   - No columnar epithelial cells
3. DO CULTURE;
   - urethra
   - cervix
   - rectum
   - oropharynx
   - conjunctiva
4. CYTOLOGY for inclusions, Pap smears: insensitive
5. Cultured in cell culture?
   - process quickly
   - only acceptable test in criminal cases
   - LESS SENSITIVE than nucleic acid based tests but MORE SPECIFIC

Question 454

Laboratory diagnosis of chlamydia trachomatis (3)

1. ◦ direct immunofluorescence (DFA)
   ◦ enzyme-linked immunoassay (ELISA)
   ◦ Utilizes antibodies directed at MOMP or LPS
   ◦ May cross react to LPS of other bacteria

2. 
◦ Nucleic acid probe (16s rRNA)
◦ PCR
◦ Ligase chain rxn (LCX)
◦ Performed on first voided urine or urethral/cervical discharge 

3. Limited value except in neonatal disease

Answer 454

1. Antigen detection
2. NAAT (nucleic acid assays); BEST TESTS TODAY
3. Serology

Question 455

Identify treatment options of chlamydia trachomatis

1. For LGV
2. For neonatal disease
3. Ocular/genital disease (2)
4. Prevention (2)
5. Control

Answer 455

1. LGV; doxycycline for 21 days
2. Neonatal disease; Erythromycin
3. Ocular/genital disease
   - Azithromycin 1gram for 1 dose
   - doxycycline for 7 days
4. Prevention
   - increased sanitation
   - safe sex practices
5. Control; treatment of contacts

Question 456

Identify family

• 5 species associated with human disease
• most important species is pneumonia (important cause of respiratory disease)
• additional pathogens cause GU disease (genitalium, hominis, urealyticum)

Answer 456

Family MYCOPLASMATACEAE

Question 457

Identify organism

• Only bacteria that have steroid in their cell membrane - they do not synthesize steroids tho
• No peptidoglycan so no cell wall
- smallest bacteria

• *Other struture xters
• size?
• unique why?
• aerobe or anaerobe? Exception?

Answer 457

Mycoplasma pneumonia

**Mycoplasma gets COLD without a COAT (cell wall)

▶ Smallest free living bacteria
▶ Unique because do not have a cell wall and cell
membrane contains sterols
◦ Because lack cell wall are pleomorphic and cannot be
classified as rods or cocci
◦ Sterols may provide added strength/stability to membrane
◦ Unable to synthesis sterol ring so require external source of
cholesterol from serum or supplemented media
▶ Facultative ANAEROBES except M. pneumoniae which is
strict AEROBE

Question 458

Mycoplasma pneumonia - pathogenesis and Immunity

1. extracellualr or intracellular pathogen?
2. virulence factor? (Protein) Results?
3. Effect of ciliated cell loss ? Results?
4. Super antigen? How?

Answer 458

1. EXTRACELLUALR pathogen that adheres to respiratory epithelium via ADHESION PROTEINS
2. TERMINAL ADHESION PROTEIN (P1); binds glycoprotein receptors of base of cilia of epithelial cells
   - results in CILIOSTASTASIS and DESTROY CILIATED EPITHELIAL CELLS
3. ▶ Loss of ciliated cells interferes with clearance of upper
   airways and lower respiratory tract becomes contaminated and irritated
   ▶ Causes the chronic cough seen in M. pneumoniae
   infections
4. M. pneumoniae acts as super antigen
   ◦ Stimulates inflammatory cells to site of infection
   ◦ Cytokine release of TNF-α, IL-1, and IL-6

Question 459

Mycoplasma pneumonia

1. Colony and transmition
2. Other epidemiology

Answer 459

1. Colonizes airways and transmitted via respiratory droplets during coughing episodes
2. ▶ Strict human pathogen
   ▶ Respiratory disease due to M. pneumoniae occurs
   worldwide throughout the year
   ▶ Proportionally more common during summer and fall
   ▶ Epidemic disease occurs every 4-8 years
   ◦ Usually start in the fall and persist for 12-30 months
   ▶ Most common in 5-15 year olds
   ▶ Not a reportable disease so true incidence is unknown

Question 460

Identify clinical syndromes that occur form mycoplasma pneumonia

1. Most common manifestation
2. Can develop bulbous hemorrhagic myringitis
3. ◦ Low grade fever, malaise, HA, and dry nonproductive cough
   ◦ Symptoms develop 2-3 weeks after exposure and can persist for weeks
4. Check x ray show terrible looking lobular infiltrates
5. Complications? (8)

Answer 460

1. MILD URTI (upper respiratory tract infections)
2. Otitis Media
3. Tracheobronchitis
4. Pneumonia - can develop in some patients
   ◦ Atypical pneumonia (often referred to as WALKING PNEUMONIA)
   ◦ Patchy bronchopneumonia on chest x-ray
5. Complications include pericarditis, hemolytic anemia, neurologic
   abnormalities, encephalitis, arthritis, ERYTHEMA MULTIFORME and Stevens-Johnson syndrome

Question 461

Mycoplasma pneumonia - Laboratory diagnoses
1.
◦ Enzyme immunoassays for IgM and IgG
◦ Four fold rise in titers suggestive of infection
◦ Commonly single serum IgM used for diagnosis results in over
diagnosis due to low specificity
◦ Specific antibody responses may last for months so single
serum sample may be misleading
◦***WHAT should be used to confirm diagnosis

2. ◦ Very sensitive
   ◦ Variable specificity due to cross reaction with non-pathogenic
   mycoplasma

Answer 461

1. Serology
   * **PAIRED SERA - should be used to confirm diagnosis
2. PCR

Question 462

Mycoplasma pneumonia - treatment, prevention and control

1. 3 abx class
2. Avoid which 2 in children
3. Reversed treatments in what conditions (3)
4. Use steroid in what conditions? (4)
5. • when does patient stop being contagious?
   • any vaccines?
   • treat other people?

Answer 462

1. Sensitive to;
   - macrolides
   - tetracyclines,
   - flouroquinolones (FQN)
2. Avoid TETRACYCLINES (>8) and FLOUROQUINOLONES (>18) in children
3. Treatment should be RESERVED for more serious disease
   ◦ Pneumonia
   ◦ Stevens-Johnson syndrome
   ◦ Neurologic disease
4. STEROIDS may be of benefit in
   - severe pulmonary disease
   - Stevens-Johnson syndrome
   - encephalitis
   - hemolytic anemia
5. ▶ Patients CONTAGIOUS as long as COUGH persists even
   with antibiotic therapy
   ▶ Isolation of hospitalized patients
   ▶ NO VACCINE AVAILABLE
   ▶ ANTIBIOTIC prophylaxis to CLOSE CONTACTS who are at
   high risk (sickle-cell disease, immunosupressed) may
   be of some benefit

Question 463

1. Identify 3 importance of vaccination

2. Identify properties of a good candidate for vaccine development (5)

Answer 463

1. A. Protect from disease
   B. Strengthen memory immune responses
   C. HERD IMMUNITY; the immmunization of a population stops the spread of infectious agents by reducing the number of susceptible hosts
2. Good candidate for vaccine
   - organism cause significant illness
   - organism exists as only one serotype
   - antibody blocks infection or systemic spread
   - organism does not have oncogenes potential
   - vaccine is heat stable so it can be transported to endemic areas

Question 464

1. Understand the differences between ACTIVE and PASSIVE immunization and cite important sources of each

A. E.g Maternal transfer of IgG, IgA in breast milk

B. Immune system is stimulated

• immune response is stimulated due to a challenge from an immunogen
• secondary immune response is faster and more effective

Answer 464

1. A. Passive immunization
   - immunity can be transferrred to a naive individual by transferring antibodies or cells e.g lymphocytes in genetically identical animals) from another individual already immune to an infection
   - important examples in nature;
   I) transplacental transfer of maternal IgG to the fetus
   II) IgA in breast milk produced during lactation

B. Active immunization
I) Immune response is stimulated due to challenge from immunogen
- exposure to infectious agents (natural immunization)
- exposure to microbes and their antigens (vaccines)
II) On subsequent challenge with virulent agent, a secondary immune response is elicited that is FASTER and MORE effective at preventing infection of the individual

Question 465

1. Uses of passive immunization (4)
2. Immune serum globulin or immunoglobulin
   A. How is human serum globulin prepared?
   B. How are hyperimmune globulins (homologous) made?
   C. Heterologous?
   D. Antitoxin treat what in the US? (2)

Answer 465

1. Uses of passive immunity
   A. Prevent disease after a known exposure
   B. Ameliorate symptoms of an ongoing disease
   C. Protect immunodeficient individuals
   D. Block action of bacterial toxins and prevent the diseases they cause
2. Immune serum globulin or immunoglobulin
   A. Human serum globulin is prepared from POOLED PLASMA and contains the normal repertoire of antibodies for an adult
   B. Hyperimmune globulins (HOMOLOGOUS) are made by SELECTING HUMAN PLASMA with high titers of desired antibody or by specifically immunizing donors to produce such antibodies e.g post exposure prophylaxis
   C. HETEROLOGOUS hyperimmune serums are produced in animals, usually HORSE (equine) and contains antibodies against only one antigen
   D. In the US, antitoxin is available for treatment of BOTULISM and DIPHTHERIA

Question 466

Identify various vaccine types (4)
- structure and method of immunogenicity

4 types of inactivated

Answer 466

Vaccine types

1. Inactivated; no risk of infection. Safe except if you allergic to vaccine components. Generate more humoral/antibody responses and less Cell mediated responses. Administered with ADJUVANT.
   A. Inactivated/killed; PRODUCED from physical or chemical process
   B. Subunit;
   C. Toxoid; diphtheria
   D. Conjugate; capsular polysaccharide (PPV and H.influenza vaccine)
2. Live/attenuated; prepared with organism limited in ability to cause disease. Mimics that natural infection that you get. LONGER LIVED IMMUNITY. E.g BCG vaccine, MMR, rotavirus
   A. Disadvantage; dangerous form immunocompromised and pregnant women
3. DNA vaccine
4. Recombinant vector vaccines

Question 467

Live vs Inactivated vaccines and immune response pattern of each vaccine type

• Use a large amount of antigen to elicit a protective antibody response but without risk of infection with the agent.
• Used to induce immunity to bacteria and viruses that cannot be attenuated, may cause recurrent infection, or have oncogenic
potential.
• Generally safe except in people who are
allergic to vaccine components.

Answer 467

Inactivated vaccines

Question 468

1. 2 ways of producing inactivated vaccines
2. Inactivated vaccines are usually administered with?
   Importance of this?

Answer 468

1. Inactivated vaccines Can be produced;
   A. Heat or chemical inactivated of bacteria, bacterial toxins or viruses
   B. Can be produced by purification or synthesis of the components or subunits of the infectious agents
   **usually generate antibody and limited cell-mediated responses
2. ADJUVANT; inactivated vaccine are usually administered with an adjuvant
   - boosts their immunogenicity by enhancing uptake by or stimulating dendritic cells and macrophages
   - some stimulate toll like receptors to activate antigen presenting cells
   - Most vaccines precipitated onto aluminum
   - MF59 (squalene microfluidized in an oil and water emulsion) and monophosphoryl lipid A (MPL) sometimes also used in newer vaccines
   - Experimental adjuvants include emulsions, virus-like particles, liposomes, bacterial cell wall components, molecular cages for antigen, polymeric surfactants, and attenuated forms of cholera toxin and E. coli lymphotoxin

Question 469

Identify vaccine type

• are made from microorganisms that have been killed
through physical or chemical processes
• Inactivated whole-cell vaccines may not always induce
an immune response and the response may not be
long lived.
• Several doses of inactivated whole-cell vaccines may
be required to evoke a sufficient immune response
• Have no risk of inducing the disease they are given
against as they do not contain live components
• Considered more stable than live attenuated vaccines

Give examples (8)

Answer 469

Killed or inactive whole bacterial or viral vaccines
**Inactivated vaccines

Compared to live;

• short lived
• more stable
• no risk of inducing disease (safer)

Currently available whole inactivated/killed;

1. WHOLE CELL PERTUSSIS
2. Typhoid
3. Cholera
4. Plague
5. POLIO (IPV - inactivated poliovirus vaccine)
6. Hepatitis A
7. Rabies
8. Whole inactivated INFLUENZA virus

Question 470

Identify vaccine type

Currently available;

• Hepatitis B
• Influenza (Hib)
• ACELLULAR pertussis
• human papilloma virus
• anthrax

**how do these work

Answer 470

SUBUNIT VACCINE (Inactivated vaccines)

• Subunit vaccine consists of the bacterial or viral
components that elicit a protective immune response
• Surface structures of bacteria and viral attachment proteins elicit protective antibodies
• T-cell antigens may also be included in a subunit vaccine

Question 471

Identify vaccine type

• diphtheria
• tetanus
• *
• made from where?
• why are they safe?

Answer 471

TOXOID vaccine (safe and stable)

• made from a toxin from bacteria that has been inactivated by treatment with formalin but that elicits an
  immune response against the toxin
• Toxoid vaccines are safe because they cannot cause the disease they prevent and there is no possibility of reversion to virulence or spread.
• They are stable; less susceptible to changes in
  temperature, humidity and light

Question 472

Identify vaccine type

• used when the antigen is a polysaccharide such as the capsular components of some bacteria (H.influenza, S. Pneumoniae)

Xters of polysaccharide

Answer 472

CONJUGATE VACCINE (inactivated)

• Polysaccharides are POOR IMMUNOGENS and are T-independent antigens; generally difficult to elicit
T-independent immune response in children under two years of age
• Polysaccharide is linked to a protein carrier (typically diphtheria toxoid, N. meningitidis outer membrane protein, or C. diphtheriae protein) that enhances immune response

Question 473

Inactivated BACTERIA vs VIRAL vaccines

1. A. E.g pertussis, typhoid, cholera, plague. No longer available in USA

B. Pneumococcal, meningococcal, salmonella typhi
OR
Acellular pertussis and anthrax

C. Diphtheria is and tetanus

Answer 473

1. Inactivated BACTERIAL vaccines
   A. WHOLE inactivated (killed) bacteria
   • whole inactivated bacterial vaccines (pertussis, typhoid,
   cholera, and plague) are no longer available in the United
   States

B. CAPSULE or PROTEIN subunits of the bacteria
• Includes polysaccharide capsule subunits such as in
pneumococcal, meningococcal, and Salmonella Typhi polysaccharide vaccines
• Includes protein subunits from acellular pertussis and
anthrax

C.TOXOID (inactivated toxins)
• Diphtheria and tetanus

Question 474

Inactivated bacteria vs viral

1. A. Polio, hep A, influenza

B. Hep B, influenza, HPV

Answer 474

1. Whole inactivated VIRAL VACCINES
   A. WHOLE inactivated viral vaccines
   – Available for polio (IPV – inactivated poliovirus vaccine), hepatitis A, and rabies
   – Inactivated whole virus influenza vaccine no longer available in US

B. SUBUNIT vaccines
– Available for hepatitis B, influenza, human
papilloma virus (HPV)

Question 475

Identify 5 disadvantages of inactivated vaccines

Answer 475

1. Immunity is not usually lifelong
2. Immunity may only be humoral and not
   cell-mediated
3. Vaccine typically does not elicit local IgA
   response
4. Booster shots are required
5. Larger doses necessary

Question 476

Identify vaccine type

• Prepared with organisms limited in their ability to cause disease, i.e. avirulent or attenuated
• Vaccines are especially useful for protection against infections caused by enveloped viruses that require T-cell immune
responses for resolution of the infection

Answer 476

LIVE VACCINES

• Immunization with a live vaccine resembles
the natural infection in that the immune
response passes through innate and T helper
responses and humoral, cellular, and memory
responses are developed.
• Immunity is generally LONG LIVED

Question 477

Identify vaccine types

– Include orally administered live, attenuated S.
typhi strain vaccine for typhoid and the bacillus Calmette-Guerin (BCG) vaccine for tuberculosis, which consists of an attenuated strain of Mycobacterium bovis, and an attenuated tularemia vaccine
– Not available in US

Answer 477

• Live bacterial vaccines

Question 478

Identify vaccine type

Consist of less virulent mutants of the wild-type
virus, viruses from other species that share antigenic determinants (such as vaccinia for smallpox and bovine rotavirus), or genetically engineered viruses lacking virulence properties

Answer 478

Live viral vaccines

Question 479

Why are live viral vaccines less virulent

Answer 479

– Wild-type viruses are attenuated by growth in
embryonated eggs or tissue culture cells at nonphysiologic temperatures (25◦ C to 34◦ C) and away from the selective pressures of the host immune response.

– These conditions select for the growth of viral strains
(mutants) that are less virulent because:
• they grow poorly at 37◦ C (e.g., measles vaccine) and
cold-adapted strains (e.g., influenza vaccine)
• they do not grow well in any human host
• they cannot escape immune control
• they may replicate at a benign site but do not disseminate
or replicate in the target tissue characteristically affected by
the disease.

Question 480

Identify 3 disadvantages of live vaccines

Answer 480

1. Dangerous for immunosuppressed people or pregnant women
2. Vaccine may revert to a virulent viral form
3. Viability of the vaccine must be maintained

Question 481

Identify vaccine type

1. • West Nile virus
2. Experimental vaccines similar to DNA vaccines,
   but they use an attenuated virus or bacterium to introduce microbial DNA to cells of the body.
3. being considered for delivering multiple doses of a
   vaccine after a single injection (eg, a single
   injection of diphtheria, tetanus, acellular pertussis
   (DTaP) vaccine could be given with timed release
   at two, four, and six months of age)

Answer 481

1. DNA vaccine
2. Recombinant vector vaccines
   – “Vector” refers to the virus or bacterium used as
   the carrier.
3. Biodegradable polymer technology

Question 482

***identify 3 vaccine myths

Answer 482

1. Autism
2. Overwhelming the immune system
3. Vaccines are not necessary; they are necessary because they provide HERD IMMUNITY and reduce exposure to antigens