Antibiotics Flashcards
1
Q
Describe the use of antibiotics
A
- Widely used and MISUSED drugs
- 20-50% questionable (1/4 to 1/2 of prescriptions are given incorrectly)
- In HOSPITALS → 30% of drug budget
- 25% of patients have recieved antibiotics within the previous 24hr
- In ITU, 50% are on antibiotics
- 50 million prescriptions per year
- 80% of human use is in the community
- 50% respiratory infecitons
- 15% UTI
2
Q
What is an antibiotic?
A
Natural product recovered from fungi and bacteria living in the soil (soil dwellers)
- This is because these organisms have to survive and compete against eachother.
- Their natural antagonism gives a selective advantage over other competitors in the soil. This will kill or inhibit the growth of other organisms
3
Q
What are most antibiotics derived from?
A
They are derived from natural products by fermentation then modified chemically.
This is carried out to → Increase pharmacological properties + increase antimicrobial effect
4
Q
What is the definition of selective toxicity?
A
When a drug has a selective action against one component and not another
5
Q
List some principles of selective toxicity for antibiotics as therapeutic agents q
A
- Based on the differences in the structure and metabolic pathways between the host and pathogen
- It harms the microorganism and not the host
- We want the target to be in the microbe (not host)
- Selective toxicity is difficult for fungi, parasites and viruses as they are obligate intracellular organisms
- It is important to note there is variation between microbes, strains within the same species
6
Q
What is the therapeutic margin?
A
We need to make sure that the dose is high enough to kill the infection without producing too much toxicity
The dose between the therapeutic/active dose and the toxic dose is called the therapuetic margin
7
Q
What is the MIC?
A
MINIMUM INHIBITORY CONCENTRATION = The concentration at which you have to give a drug in order for it to be effective microbiologically
8
Q
Describe therapeutic indexes
A
-
Narrow Therapeutic Index = A small range of doses at which medication provides benefits without causing severe and fatal complications
- e.g vancomycin and aminoglycosides
- Will have to measure blood levels to make sure antibiotic levels are enough to maintain the MIC but not cause toxicity
- e.g vancomycin and aminoglycosides
- Wide Therapeutic Index = A large range of doses at which the medication will provide benefits without causing severe and potentially fatal complications
9
Q
What is microbial antagonism
A
- Concept where one microorganism is producing a substance that inhibits the growth of another
- This will maintain flora as they have complex interactions between themselves that maintain them at a certain level
- They limit growth of competitors + flora
10
Q
Give an example where microbiota can become disrupted
A
- Antibiotic use can provide a competitive advantage to spore forming anaerobes compared to non-spore forming anaerobes
- They can also mess up the balance of bacteria in your gut
- e.g clindamycin, broad spectrum lactams and fluoroquinolones
- These can lead to antibiotic associated colitis, psuedomembranous colitis caused by the bacteria Clostridium difficile
11
Q
What are symptoms of C.difficle?
A
- Ulcerations - inflammation
- Severe diarrhoea
- Serious hospital cross-infection risks
- See lots of pseudomembranes filled with leucocytes, fibrin, mucous and cell debris
- This means colonocytes can no longer absorb water leading to acute watery diarrhoea
12
Q
Explain the interaction of antibiotics with the immune system
A
- Antibiotics will not work alone (ANTIBIOTICS + IMMUNITY → BACTERIAL CLEARANCE)
- The antibiotics in an immunocompetent patient will partly rely on immune system to clear infection
- Seen as in patients who are immunocompromised (difficult to treat their infections with purely ABs)
- E.g. Cancer, chemotherapy, transplantation, myeloma, leukaemia, HIV with low CD4, neutropenic, asplenic, renal disease, diabetics, alcoholics
13
Q
What are the three ways antibiotics can be classfied?
A
- Type of activity (bactericidal vs bacteriostatic + spectrum of activity)
- Structure
- Target site of activity
14
Q
Describe the difference between bactericidal and bacteriostatic antibiotics
A
-
Bacteriocidal
- Kill bacteria
- Used when the host defense mechanisms are impaired
- Required in more serios infections → Endocarditis and kidney infections
-
Bacteriostatic
- Inhibit bacteria
- Used when the host defense mechanisms are intact
15
Q
Describe the spectrum of activity in antibiotics
A
-
BROAD SPECTRUM ANTIBIOTICS
- Effective against many different types of bacteria
- For example, à CEFOTAXIME
- Effective against many different types of bacteria
-
NARROW SPECTRUM ANTIBIOTICS
- Effective against very few types of bacteria
- For example, à Penicillin G
- Effective against very few types of bacteria
16
Q
Describe cephalosporins
A
- Cephalosporins are modified penicillins
- This illustrates the idea that as we modify antibiotics they change their efficiency against different organisms. It is a balance
- We now use different generation cephalosporins to treat different microorganisms based on their efficacy
17
Q
Describe how antibiotics can be classified depending on their molecular structure
A
- Antibiotics can be put into famillies of drugs depending on their molecular structure
- For example tetracyclines and beta lactams
18
Q
Describe the beta lactam ring
A
- Both penicillins and cephalosporins contain a beta lactam ring
- Hence why penicillin or cephalosporins are reffered to as beta lactams
- They act as natural competitor substrates for enzymes involved in bacterial cell wall
- Some bacteria have acquired resistance to beta lactams by acquiring beta-lactamases which degrade the beta lactam structure
- Once it has been destroyed the antibiotics will have no antimicrobial properties whatsoever
19
Q
Remind yourself on the structure of a bacterium
A
20
Q
How do antibiotics target cell wall synthesis?
A
- These bacteria will inhibit cell wall synthesis. If it cant make its cell wall it will die and be cleared
- Examples
- Vancomycin, Cephalosporins and penicillins
21
Q
Give an example of a cephalosporin
A
Cefuroxime
- Good activity against gram + and gram - bacteria
22
Q
Describe the antibiotic target against protein synthesis in bacteria?
A
- Erythromycin, Clindamycin (50S), Tetracyclin (30S) , Gentamycin
- Different antibiotics will bind to different ribosomal subunits dependant on the antibiotic
- These exhibit a good selective toxicity because they can inhibit bacterial ribosomes without affecting our eukaryotic ribosomes
23
Q
Explain how antibiotics can target DNA and RNA processing in bacteria?
A
- Inhibit the way DNA replicates or transcription of mRNA
- Enzymes in these processes are slightly different to those in eukaryotes and hence display a good selective toxicity
- Quinolones will target and inhibit DNA gyrase
- Rifampicin target enzyme that makes bacterial mRNA (DNA dependant RNA polymerase)
24
Q
How are antibiotics a target in folic acid metabolism?
A
- Trimethoprim and sulfonamide
- These inhibit the folic acid metabolism
- Humans cannot synthesise folic acid we get it through our diet
- If bacteria cant make folic acid it will lose its cofactors for multiple enzymes in its metabolism and die
- Good selective target as the enzymes which make folic acid in bacteria are not present in humans (we lack the abillity to synthesise folic acid)
25
How are antibiotics a target in cell membrane damage and free radical damage?
* Cell membrane damage
* →**Colistin (highly toxic)**
* These antibiotics damage the membrane of bacteria
* However, these drugs have a poor selective toxicity because bacterial membranes are similar to eukaryotic membranes which means some of them can be toxic
* Generation of Free radicals
* → **Metronidazole** (used to treat anerobic bacteria)
* Free radicals will damage many components of the cell, mainly DNA, but they can also damage membranes, lipids, enzymes involved in metabolism
26
Give examples of different types of antibiotics based on their cellular targets
1) CELL WALL SYNTHESIS
* Vancomycin, Cephalosporins, Penicillins
2) PROTEIN SYNTHESIS INHIBITORS
* Clindamycin, Erythromycin (50S)
* Streptamycin, Tetracyclin (30S)
3) DNA AND RNA PROCESSING
* Quinolone (DNA gyrase)
* Rifampin (DNA-dependant RNA polymerase)
4) FOLIC ACID METABOLISM
* Trimethoprim
* Sulfonamides
5) CELL MEMBRANE DAMAGING
* Colistin
6) GENERATE FREE RADICALS
* Metronidazole
27
Why can some antibiotics only work against gram posotive bacteria and not gram negative?
* Gram + bacteria have a massive area of peptidoglycan sitting on top of the bacterial membrane
* Inside the peptidoglycan there are lipoteichoic acids that transverse the wall and anchored in the membrane
* The cell wall is a **porous structure** which allows antibiotics to get to the site allowing AB's to work
* Gram - bacteria the peptidoglycan is located in the **periplasmic space**
* It is covered by an **outer membrane** which is an **impermeabillity barrier**
* Therefore anything can only get across the barrier via **porins**
28
Describe peptidoglycan cell wall synthesis
1. Start off with a precursor m**onomer of a di-polysaccharide with five peptides**
2. The last two peptides in the monomer are **(D-ala)** alanines which are specific to bacteria
1. Some drugs will inhibit the incorporation of terminal D-ala into the cell wall precursor
3. Once made it will go across the cytoplasm by linking to a lipid transport molecule (can also be inhibited by certain ABs)
4. Enzymes on the cell wall will recognise D-ala and cleave the terminal one off
5. The remainder of the chain will be linked to the long peptidoglycan chain via **trans-carboxypeptidase**s these are only found in bacterial cell walls
1. Beta lactams will inhibit enzymes involved in cross-linking of the growing peptidoglycan chain
6. Antibiotics will work by inhibiting these specific enzymes which create the peptidoglycan layer
29
Use the inhibitors of bacterial cell wall synthesis to explain how antibiotics are able to carry out their effect
* Antibiotics are often structural mimics of natural substrates for bacterial enzymes
* For example, the beta-lactam backbone is nearly identical to the D-ala D-ala structure
30
Describe the Action of beta-lactams on PBP in Gram -ve bacteria
* Beta lactams will enter the cell via a porin and inhibit the penicillin binding protein transpeptidase
* This will prevent peptidoglycan cross linking cell wall synthesis
* If this is inhibited it triggers induction of autolytic enzymes leading to bacterial death
31
Describe the mechanism of action of folic acid synthesis inhibitors
* There are multiple enzymes which will lead to the production of **tetrahydrofolic acid**
* Bacteria will start off folic acid synthesis by using dihydropteroate diphosphate and p-aminobenzoic acid
* Sulfonamide has a similar moelcular structure to PABA therefore it will act like a competitive inhibitor for the enzyme dihydropteroate synthetase
* This will produce dihydropteroic acid
* This will then be converted by a number of steps into dihydrofolic acid
* From dihydrofolic acid it will be converted to tetrahydrofolic acid via **dihydrofolate reductase**
* Human DHFR is less inhibited = less selective toxicity
32
When do we use antibiotics?
* Treatment of bacterial infections
* Prophylaxis
* Close contacts of transmissible infections
* Decrease carriage rates (increase 80% in outbreaks)
* Prevent of infection e,g meningitis, tuberculosis
* Peri-operatively especially during gut surgery because of the vast microbiota present here
* People with increased susceptibility to infection
* (people with no spleens or sickle cell)
33
What is the MIC dependant on?
Strains are always tested to make sure we are aware of the MIC of that organism
* The MIC will depend on the age, weight, renal and liver function of the patient and the severity of the infection
* Depend on the susceptibility of the organism
