Week 103 Swollen finger Flashcards
(99 cards)
1
Q
What are signs of acute inflammation?
A
- Redness
- Swelling
- Pain
- Heat
- Loss of function
2
Q
Describe the 1st layer of immune defense (1/3)
A
External barriers e.g. skin and mucous membranes
3
Q
Describe the 2nd layer of immune defense (2/3)
A
Innate immune system: cellular components e.g. phagocytes, degranulating cells and NK cells
Soluble components e.g. complement, cytokines, antimicrobial peptides and acute phase proteins.
All of this leads to non-self recognition, inflammation, phagocytosis and killing of microbes
4
Q
Describe the 3rd layer of immune defense (3/3)
A
Adaptive immune system:
Soluble components: Antibodies
Cellular components: B and T cells
These all leads to non-self recognition (Ag specific), block microbial adhesion, neutralising toxins, chronic inflammation and killing of microbes
5
Q
How is a pathogen phagocytosed?
A
The pathogen is phagocytosed or taken up by the macrophage. This internalised vacuole is known as a phagosome. Lysosomes, that contain digestive enzymes and sit in the cytoplasm of the cell, fuse with the phagosome to form a phagolysosome and the pathogen is broken into waste material. The vacuole then fuses with the plasma membrane to expel the waste material from the cell
6
Q
What do dendritic cells help do?
A
Antigen presentation: phagocytosis occurs followed by degradation of the microbe
The Ag is then presented on the surface of the dendritic cell
7
Q
Describe mast cell degranulation
A
Mast cells are found in connective tissues around our external barriers (e.g.
skin, respiratory tract , GI tract etc) and contain lots of granules that discharge
their contents externally upon detection of a ‘foreign’ substance. The granules
contain a number of different substances, such as histamine, that under normal
circumstances are protective; upon degranulation they chemically attract other
immune cells to the area under attack and thus contribute to the inflammatory
response. However, in certain individuals, these cells can also contribute to
allergic and inflammatory diseases
8
Q
What is the name of a clump of pus?
A
An abscess
9
Q
How does an abscess form?
A
1. The pathogen is deposited in the tissue. 2. Blood vessels dilate and leukocytes migrate to the multiplying pathogens. 3. This results in pus formation and clotting occurs in blood vessels adjacent to infection. 4. Build-up of pressure causes abscess to expand in direction of least resistance; if it reaches a body surface, it may rupture discharging pus
10
Q
Describe features of cytokines
A
They are integral to inflammation, innate and adaptive immunity.
They are:
- secreted proteins
- have many cell sources
- structurally diverse
- diverse functions
- small peptides, folded 3D structure (~100-150 amino acids)
- produced at very low concs
- usually act over small distances (cell-cell: paracrine)
11
Q
What are major functions of cytokines?
A
Major Cytokine Functions:
cause growth/ differentiation of immune cells
stimulate an effector response (immunity)
stimulate directed migration of immune cells
regulate the immune response (e.g. suppression)
12
Q
What do cytokines bind to?
A
Cognate cellular receptors
Extracellular domain= cytokine binding
cytoplasmic domain= intracellular binding
13
Q
Name examples of cytokines and their receptor
A
IL-1Beta –> IL-1R
TNF-alpha (homo-trimer)
14
Q
Name and describe 3 structurally diverse cytokine receptor families that induce different intracellular events
A
Hematopoietin family:
- 2 distinct peptide chains
- activates Jak-STAT proteins
Chemokine family:
- single peptide chain
- activates G proteins
TNF family
- 3 identical chains
- activates NF-kappa beta
15
Q
Describe what’s present in infected pus
A
Extracellular fluid
Lymph
Neutrophils
16
Q
Name examples of inflammatory mediators
A
Cytokines: TNF-alpha, IL-8, IL1-beta, IL-6 (early tissue response 24-48 hrs)
Prostaglandins
Leukotrienes
17
Q
What are the effects of major cytokines during tissue inflammation and immune activation?
A
- macrophage activation (microbial killing)
- tissue inflammation, innate immunity
- Ag presentation (T-cell activation)
- Adaptive immunity (delayed response)
18
Q
What does TNF-alpha do?
A
Plasma leakage–> vasodilation
19
Q
What does IL1-beta do?
A
(PGE2)—> fever response
20
Q
What does IL-6 do?
A
acute phase response - fibrinogen, CRP, MBL
21
Q
What does IL-8 do?
A
Neutorphil chemotaxis
22
Q
What chemicals activate antibody synthesis?
A
IL-4 and Th2-type
23
Q
What chemicals activate macrophages?
A
IFN-gamma and Th1-type
24
Q
What 3 ways can the complement system be activated?
A
1 - Classical (with Abs)
2- Alternative (spontaneous generation of active C3b complement fragments)
3- Lectin (with mannose binding lectin) pathway activation
25
What are three ways the complement cascade helps defend against microbes?
(1) formation of the
smaller or minor fragments that contribute to inflammation (e.g. C3a, C5a)
```
(2) formation of the larger or
major fragments (C3b) which function as opsonins (which leads to phagocytosis)
```
(3) formation of the
membrane attack complex (C5b678poly9) that ultimately causes lysis of the microbe
26
What does C1 inhibitor (C1 INB) do?
This plasma protein is a proteolytic enzyme (protease). As the name suggests it de-activates antibodybound
C1 of the classical pathway, stripping it of the components that activate C4 and C2. As C1 INB is a
plasma component, it regulates the overall amount of activity in the classical pathway.
27
What does Factor H with Factor I do?
These two plasma proteins are both proteases that work together. Factor H (FH) binds to C3b breaking
the bond between C3b and Bb, then Factor I (FI) breaks C3b de-activating it. They are important in
causing the breakdown of C3 convertases of the alternative pathway. As they are both plasma
components, they regulate the overall amount of activity in the alternative pathway.
28
What does C4 binding protein (C4BP) with Factor I do?
These two plasma proteins work together to de-activate C3 convertases in the lectin and classical
pathways. C4BP binds to C4b displacing C2b, then Factor I (FI) breaks C4b deactivating it. As C4BP and
FI are both plasma components, they regulate the overall amount of activity of the lectin and classical
pathways.
29
What does Membrane cofactor protein (MCP
| ) with factor I do?
MCP is found on host cells specifically the membranes of leukocytes, epithelial cells and endothelial
cells. When either C3 or C4 attach to cells that contain this protein, it will bind to them, factor I (FI) is
then able to cleave the fragment, deactivating it and preventing the formation of C3 convertase in all
three pathways. As MCP is found on host cell membranes, it minimises the damage to host cells, and,
thus, directs the activity of the complement system.
30
What does Decay-accelerating factor (DAF) with factor I do?
DAF is found on host cells specifically the membranes of blood cells, epithelial cells and endothelial cells.
DAF binds to C4b displacing C2b in the classical pathway (Fig 5) or C3b displacing Bb in the alternative
pathway (Fig 6) then Factor I (FI) break the C4b or C3b proteins deactivating them. Thus, DAF is
important in causing the breakdown of C3 convertases of all complement pathways. As DAF is found on
host cell membranes, it minimises the damage to host cells, and, thus, directs the activity of the
complement system.
31
What does CD59 do?
CD59 is found on host cells specifically the membranes of blood cells, epithelial cells and endothelial
cells. During the formation of the MAC, it attaches to the C5b component of the C5bC6C7 preventing
the C9 fragments assembling. As CD59 is found on host cell membranes, it minimises the damage to
host cells, and, thus, restricts the formation of the MAC to foreign cells.
32
What does S protein do?
```
S protein (SP) is found in plasma. It binds to the C7 component as the MAC is forming. This binding
prevents the C5bC6C7 complex from inserting into the plasma membrane and inhibits the formation of
the MAC. As the protein is found in plasma, it regulates the overall activity of MAC formation.
```
33
When does the complement system cause us problems?
| sorry dis one long
1) Complement deficiencies
Genetic deficiencies or defects in any of the protein components can lead to abnormal patterns of
complement activation/regulation. This can be the result of :-
Deficiencies in any of the early pathway components (C1, C2, C3, C4, Factor B, Factor D,
Properdin, MBL). This can cause failure to clear immune complexes
or an increased
susceptibility to infection.
Deficiencies in any of the terminal complement components i.e. those that make up the MAC (C5,
C6, C7, C8, C9). This tends to cause an increased susceptibility to disseminated infections by
Neisseria bacteria.
Deficiencies in the complement regulatory proteins (C1 IHB, Factor I, Factor H, C4 BP and S
protein, MCP, DAF, CR1, CD59). This causes problems from excess inflammation and cell lysis.
Deficiencies in complement receptors (type 1-4). These receptors are vital in mediating the
biological activities between complement fragments and various cell types (e.g. Phagocytic cells
use CR1 to recognise, bind to and internalise C3b or C4b coated particles)
2) Pathological effects of a normal functioning complement system.
Despite being properly regulated and appropriated activated the complement system can cause
significant damage to tissues. This might come about when you:
Have a chronic infection (i.e. infectious organisms that persist in the body)
Make antibodies to components of your own cells (autoimmune conditions)
Have immune complexes deposited in tissues (immune complex disease)
34
Name cellular examples of anatomical and physical barriers of the IS
Cilliary clearance
Low stomach pH
Skin, intestinal movement, oscillation of broncho-pulmonary cilia etc – prevent pathogens from entering and/or establishing in the body
35
Name innate immunity cells
```
NLRs
TLRs
Complement
Neutrophils
Host defence peptides
Dendritic cells
```
36
Name adaptive immunity cells
T cells
| B cells
37
Name secreted molecules (anti-microbials) of our body
Chemical: Organic acids in skin secretions; lysozyme in oro-nasopharyngeal and lacrimal secretions; bile acids in the GI tract; transferrin; interferons; complement; cytokines (e.g. TNFa); chemokines
38
Name innate immunity surface barriers
```
Tears (lysozyme)
Skin
Acidic pH
Sweat, oil, fatty acid secretions
Large intestine normal flora
Saliva washes microbes from teeth
Respiratory tract (mucus and cilia)
Bladder (urine washes microbes from urethra)
```
39
What do microbes express?
Evolutionary conserved patterns of molecules termed
PAMPS (pathogen associated molecular patterns)
that are recognied by PRRs (pattern recognition receptors) expressed by cells of the innate immune system
40
What are the principles of PRRs?
1. Those that mediate engulfment/ phagocytic uptake of pathogen.
2. Those that activate pro-inflammatory pathways.
41
Name PPRs involved in Receptors mediating engulfment/phagocytosis
Scavenger receptors
Mannose receptors
b-glucan receptors (fungi)
Fc and complement receptors (opsonised particles)
42
Name PPRs involved in Receptors mediating inflammatory response
Toll-like receptors (TLRs)
| CLRs, RLRs, NLRs
43
Describe TLRs
Key proteins that enable mammals (even if immunologically naïve; germ line encoded) to detect microbes
At least 11 mammalian TLRs
First one identified on basis of homology to a receptor essential for host defence against fungal infection in Drosophila.
Pivotal role in host defence but increasingly implicated in inflammatory disorders
44
Describe the ligand for TLR 1,2, 6
Zymosan (fungi); peptidoglycan (Gram +ve bacteria)
45
Describe the ligand for TLR 3
Double stranded RNA
46
Describe the ligand for TLR4
Lipopolysaccharide of Gram -ve bacteria
47
Describe the ligand for TLR5
Flagellin
48
Describe the ligand for TLR7/8
Single stranded RNA/ anti-viral compounds
49
Describe the ligand for TLR9
Unmethylated DNA sequences rich in C and G bases
50
Describe the ligand for TLR10
Not yet known ?Listeria/anti-inflammatory
51
Describe TLR11
Not active in humans (mice – profilin)
52
What are DAMPs
DAMPs – danger-associated molecular patterns: self molecules released in conditions of cellular damage (e.g. mitochondria, RNA) or stress or formed by pathogen-mediated modification of host proteins that can interact with the PRRs of the innate immune system.
53
What causes inflammation?
Infection
Tissue damage/trauma
Irritants (including allergy)
54
Describe the Normal Immune response
```
Innate
– Non-specific
– Early / ‘short lived’
– Pattern recognition
– Cells (eg neutrophils), proteins
• Adaptive / acquired
– Specific
– Delayed / memory
– Specific molecule recognition
– Cells (eg T-cells), antibodies
```
55
What does the immune system cause a reaction?
```
Damage / organism
• Innate response
• Cytokines / phagocytic / antigen presenting cells
• Antigen presentation
• Adaptive response
– Cellular (T-cells – cytotoxic and helper)
– Humoral (B-cells) – antibodies
• Resolution
```
56
Describe T cell activation
– All T-cell receptors different
– Potentially 1013 different T-cells each capable of
recognising different antigen
– Antigen presenting cells ‘present’ antigen to Tcells
and activate them.
– T-helper cells (CD4) – help B-cells produce
antibodies
– Cytotoxic T-cells (CD8) – directly kill infected cells.
57
Describe cytokines (again :) )
Small molecules which participate in cell
signalling
• Mediate local effects of immune response
• Mediate systemic effects of immune response
• Control cell chemotaxis, growth, differentiation
• Control the activation and resolution of
inflammation and immune response
• Complex
– Main players important
• Increasingly important in treating disease
58
What does TNF-alpha, IL-1 and IL-6 do?
```
Mainly innate and
link inflammation and
immunity. Proinflammatory.
Cause
fever, acute phase
response - systemic
effects
```
59
What does IL-2, IL-4 and IF-gamma do?
Mainly adaptive.
Control cell function
and differentiation
60
What is worse than an antigen?
A superantigen
61
What are the 4 tupes of hypersensitivity?
– I – Immediate
– II – Cytotoxic (antibody)
– III – Immune complex
– IV – Delayed (cell mediated)
62
What is autoimmunity?
• Immune response directed against own tissue
• Break in ‘tolerance’
• Relatively common
• Potentially life threatening without treatment
in many cases
• Various mechanisms, but usually multifactorial
– interaction of genetic and environmental
triggers.
63
What is the effect of autoimmunity?
Depend on target organ
– Organ specific
• Type I diabetes, Vitiligo, Pernicious anaemia, addisons
disease, Psoriasis, myasthenia gravis, Ulcerative colitis
– Non-Organ specific
• Lupus, Rheumatoid arthritis, systemic sclerosis, vasculitis
– Overlap
• Goodpastures syndrome
64
How can you treat autoimmune Disease?
Immunosupression
– Blanket bomb
• Generic treatments
– Corticosteroids
– ‘traditional’ drugs, eg methotrexate, azathioprine,
Mycophenolate
• Usually chemical compounds
– Magic bullets
• Target specific, individual molecules
• Require detailed understanding of immune process
• Usually proteins (antibodies / receptors)
Glucocorticoids (Cortisol / Hydrocortisone /
Prednisolone, etc)
– First used in early 1950’s
– Effects include
• Inhibition of innate effects (prostoglandins and
leukotienes) – reduce inflammation
• Inhibition and reduction of T-cells
• Inhibition of B-cells / antibody production
– Very potent and effective
– Side effects!
```
Methotrexate
– Inhibits folic acid synthesis
– Effect on dividing cells
• Everywhere
– Effects on T-cells
• Azathioprine
– Inhibits DNA synthesis
– Effect on dividing cells – B/T-cells
```
65
Describe Class 1 antimicrobials
Reactions that utilise glucose and other carbon sources are used
to produce ATP and simple carbon compounds. (not great as
humans use this, not selective for pathogens)
66
Describe Class 2 antimicrobials
```
Pathways utilising energy and class I compounds to make small
molecules, amino acids & nucleotides. (better, as some non
human pathways exist, some selectivity based on affinity)
```
67
Describe Class 3 antimicrobials
Pathways that convert small molecules into macromolecules
such as proteins, nucleic acids and peptides. (Great, lots of non
human targets and selective for pathogens)
68
Describe prokaryotes
Cells ‘without a nuclei’, mainly bacterial.
– Cell wall (Peptidoglycan, Gram +ve & -ve)
– Genetic material (not surrounded by nuclear
envelope).
– Protein synthesis (30S & 50S subunits, make 70S).
– Metabolic pathways (aerobic & anaerobic)
69
What 2 ways can antimicrobials work?
– Direct killing of the organism (bactericidal)
• Does not require host immune system
– Inhibiting cell function (bacteriostatic)
• Requires the host immune system to clear the
pathogen
70
Name Four main ways that antimicrobial chemotherapy
| targets the bacteria
```
– Disruption of cell wall
• Very different to human cell membrane
– Inhibition of nucleic acid synthesis
• No nuclear membrane and supercoiling
– Inhibition of protein synthesis
• Different ribosome structure
– Antimetabolite activity
• Unable to utilise environmental folate
```
71
Name ABs that cause cell wall peptidoglycan disruption
beta-lactams
| Vancomycin
72
Name ABs that disrupt DNA supercoiling in anaerobic organisms
Metronidazole
73
Name ABs that disrupt SNA supercoiling
Gyrase inhibitors (quinolones)
74
Name ABs that inhibit protein metabolism
sulphonamides
| trimethoprim
75
Name ABs that inhibit protein synthesis at various sites
```
macrolides
aminoglycosides
tetracycline
tigecycline
rifampacin
chloramphenicol
oxazolidones
```
76
What does “bactericidal”mean?
KILLS BACTERIA MUAHAHAHAH
Interference of cell wall synthesis and inhibit crucial enzymes.
• Destruction of existing DNA
77
What does “bacteriostatic”mean?
– “bacteriostatic” means that the agent prevents the growth of
bacteria (it keeps them in the stationary phase of growth)
– Bacteriostatic antibiotics prevent further replication of bacteria,
and therefore rely on an intact immune system to clear the
infection
• Inhibiting metabolic pathways
Bactericidal drugs don’t kill all of the bacterial load
• Bacteriostatic drugs often will kill some of the bacterial load but not
enough to be called bactericidal
78
What is minimum inhibitory concentrations defined as?
Potency
79
What is minimum bactericidal concentrations defined as?
‘the lowest concentration of antimicrobial that will prevent
the growth of an organism after subculture on to antibioticfree
media.’
80
Describe gram +ve cell wall
```
Gram-Positive (Simple)
– 15-50nm
– 50% peptidoglycan
– 40-45% acidic polymer
– 5-10% proteins &
polysaccharides
```
81
Describe gram -ve cell wall
```
Gram-Negative (Complex)
– Periplasmic space
– 2 nm peptidoglcan
– Outer membrane
– Complex polysaccharides
```
82
Describe Penicillins
Benzylpenicillin, flucloxacillin, amoxicillin • Bactericidal action – Mainly aerobic Gram+ve and a more limited
Gram
-ve action
• Pharmacodynamics – Interfere with synthesis of bacterial cell wall
peptidoglycan
– Inhibit transpeptidation enzyme that
crosslinks the peptide chains
– Inactivation of an inhibitor of autolytic
enzymes
– Inhibited by
β
-lactamases (clavulanic acid,
co
-amoxiclav)
– Unwanted effects: Hypersensitivity reactions
(can be severe) Degredation products
• Pharmacokinetics – Penicillin G is destroyed by gastric acid so
I.M. or I.V.
– Penicillin V is more stable so can be given
P.O.
– Wide distribution, not brain* – Eliminated mainly unchanged by kidneys in
urine (recovery
✝
)
83
Describe Cephalosporins
```
Cefuroxime, cefotaxime, cefalexin
• Bactericidal action
– Broad spectrum, mainly Gram+ve some
drugs are active against Gram-ve
• Pharmacodynamics
– Same activity as β-lactams
– More resistant to inhibition by β-
lactamases
– Unwanted effects: Hypersensitivity &
drug induce alcohol sensitivity
• Pharmacokinetics
– Wide distribution and cross BBB
– Parentally, I.M. or I.V.
– Some P.O. Cefalexin
– Excreted via kidney, some in bile
(enterohepatic recurculation
```
84
Describe Glycopeptides
```
Vancomycin, teicoplanin
• Bactericidal action
– Broad spectrum, mainly
Gram+ve
– Vancomycin (MRSA)
• Pharmacodynamics
– Inhibits cell wall synthesis by
building block unit from the
carrier
– Building using the C55 lipid
carrier to cross the membrane
– Ototoxicity
• Pharmacokinetics
– Not absorbed from GI tract
(topical)
– Systemic use is I.V.
– Excreted by kidney
```
85
Describe Microbial Nucleic Acid Synthesis
```
Bacterial DNA has no nuclear
envelope
• DNA is supercoiled, +ve
supercoiling stabalises the
DNA and –ve supercoiling
allows replication and reduces
torsional stress on the DNA
strands (important for circular
DNA, plasmids)
• DNA gyrase is essential to
supercoil DNA, topoisomerase
II produce negative
supercoiling to allow
transcription and replication
```
86
Describe Fluoroquinolones
```
Ciprofloxacin, Norfloxacin
• Bactericidal
– broad spectrum of activity,
Gram+ve and Gram-ve. Mainly
aerobic bacteria
• Pharmacodynamics
– Inhibit replication of bacterial DNA
– DNA gyrase and DNA
topoisomerase II
– GI disturbance, C. Diff overgrowth
• Pharmacokinetics
– Mainly oral; however I.V. avaliable
– Wide distribution with the
exception of CSF*
– Eliminated by kidney
```
87
Describe Microbial Metabolism
```
Folate pathway (used for DNA
synthesis)
– Humans use dietary folate
(already made)
– Bacteria use synthesized folate
(must make it as cant uptake it)
as they don’t have the
transporter protein
• Tetrahyrofolate (co-factor in
thymidylate synthesis)
– Similar pathways in Human and
Bacteria
– Bacteria dihydrofolate reductase
is more sensitive than human,
DHFT, to inhibition by
trimethoprim
```
88
Describe the folate pathway
```
p-aminobenzoic acid + Pteridine
+
Dihydropteroate
synthetase
=
Dihydropteroic acid
+
Didydrofolate
synthetase
=
Dihydrofolic acid
+
Dihydrofolate
reductase
=
Tetrahydrofolic acid
=
Thymidine
Methionine
Purines
=
DNA
```
89
Describe Sulfonamides
```
• Sulfamethoxazole*, sulfadiazine
• Bacteriostatic action
– Mainly T. gondii, P. jirovecii
• Pharmacodynamics
– Compete with PABA for the
enzyme dihydroproteate
synthetase enzyme.
– Unwanted effects can be serious;
hepatitis, toxic epidermal
necrolysis, rashes and anaphylaxis.
• Pharmacokinetics
– Sulfonamides are usually given
orally and widely distributed.
– Metaboli
```
90
Describe Trimethoprim
```
• Bacteriostatic action
Trimethoprim
– Broad spectrum active against
most common bacteria pathogens
and protozoa, p. jerovicii*
• Pharmacodynamics
– Closely resembles the pteridine
moiety of folate
– Competes for the active site of the
enzyme
– More sensitive for bacterial DHFS
than human (handy)
– Can be given with Sulfonamides to
increase activity (Co-trimoxazole)
• Pharmacokinetics
– Given orally and widely
distributed throughout tissues;
high concentrations in lung,
kidneys and CSF.
– Excreted by kidney
```
91
Describe Microbial Protein Synthesis
```
Bacterial cells have a
different ribosome
structure
– 50S and 30S subunits
combine to a 70S ribosome
(Human 60S & 40S)
– mRNA transcribed by
ribosome to amino acid
chain and growing protein
structure
• Subunits provide a unique
target for antimicrobial
agents
• Bacteriostatic or
Bacteriocidal dependent on
the structural protein that
is affected.
```
92
Describe Aminoglycosides
```
• Gentamicin, streptomycin
• Bactericidal
– broad spectrum mainly against
aerobic Gram-ve & Gram+ve
species
• Pharmacodynamics
– Inhibit bacterial protein synthesis
Bind to 30S subunit of ribosomes
– Misreading of mRNA codons
– Causes problems with production
of proteins for bacterial cell
function
– Serious and dose related
ototoxicity & nephrotoxic
• Pharmacokinetics
– Highly polar so not absorbed via
GIT
– I.M or I.V.
– Excreted via kidney, 50-60% of
dose is unchanged
```
93
Describe Macrolides
```
• Erythromycin, clarithromycin
• Bacteriostatic
– Broad spectrum Gram+ve
bacteria
• Pharmacodynamics
– Inhibit ribosome translocation
– Bind to 50S subunit of bacterial
ribosome
– Same site as cloramphenicol and
clinidamycin, competition
between drugs
– GI disturbance and overgrowth
of bacteria
• Pharmacokinetics
– P.O. or I.V.
– Don’t cross BBB
– Concentrates in phagocytes (40x)
– Inactivated by liver and
eliminated in bile
```
94
Describe Nitrofurantoin
```
Bacteriocidal
– Gram+ve & Gram-ve
• Pharmacodynamics
– Binds to 50S subunit of
bacterial ribosome
– Damages bacterial DNA
– GI effects, Pulmonary
toxicity & peripheral
neuropathy
• Pharmacokinetics
– Oral administration
– Only acheives antibactrial
concentrations in urine
(UTIs)
– Excreted in urine
```
95
Describe • Metronidazole
Inhibits DNA synthesis and breaks down existing
| DNA
96
Describe fusidic acid
Steroid drug that inhibits protein synthesis
97
Describe Oxazolidinones
New class of drug (first for several decades)
– Inhibits N-formylmethionyl-tRNA formation on the
70S bacterial ribosome
98
Name Common Severe Unwanted Effects of ABs
• Allergy (severe immediate reaction)
– Penicillin allergy is the most commonly reported medication allergy.
– Penicillin in the intact form is not very allergenic, but under physiologic conditions, penicillins
spontaneously degrade to a number of reactive intermediates that covalently bind to carrier
proteins in the tissue and serum. Sensitized individuals have a widespread activation of mast
cells and basophils that result in release of an array of vasoactive mediators
• Gastrointestinal disturbance
– Disturbance results in diminishing the natural defense mechanisms provided by the colonic
microbial ecosystem, making the host vulnerable to infection by commensal microorganisms
or nosocomial pathogens (C. diff)
• Ototoxicity
– Many have a damaging effect on the ear possibly binding to NMDA receptors in ear or
mitochondrial ribosomes also ROS can be produced (N-acetylcysteine could protect)
– Hearing loss can be temporary but is usually irreversible with most agents.
– The usual time of onset is often unpredictable, and marked hearing loss can occur even after a
single dose
• Nephrotoxicity
– Principal cause of drug-associated nephropathy
– Drug-induced immunologic process and direct action or due to drug accumulation
99
What is the problem with using ABs?
DRUG resistance
• Bacteria have been exposed to antimicrobial chemotherapy for 70 years and they evolve! – Short generation times allows fairly rapid evolutionary response – Three main mechanisms of transfer • Transfer of resistant bacteria between hosts • Transfer of bacterial resistance genes between bacteria (Plasmids) • Transfer of resistance genes within bacteria (Transposons) • Mechanisms of bacterial resistance – Production of enzymes (β-lactamases) – Alteration of drug binding sites (50S alteration binding for erythromycin) – Reduction of drug uptake (membrane proteins to pump drug out) – Alteration of enzyme pathways (DHFR affinity for trimethoprim) • Main approach to combat resistance is ‘Antibiotic stewardship'
